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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

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Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 [email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Vanessa Le Berre, Anne Malo, Carol Moreau, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski. Philippe Dessen is the Database Director (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008.

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Jean-Loup Huret (Poitiers, France) Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Brigitte Debuire (Villejuif, France) Deep Insights Section Marc De Braekeleer (Brest, France) Genes / Leukaemia Sections François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections Adriana Zamecnikova (Kuwait) Leukaemia Section

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Volume 19, Number 1, January 2015

Table of contents

Gene Section

CXXC5 (CXXC finger protein 5) 1 Pelin Yasar, Mesut Muyan EIF4B (eukaryotic translation initiation factor 4B) 4 Thomas Sbarrato, Emilie Horvilleur, Tuija Pöyry, Anne E Willis FOXQ1 (forkhead box Q1) 11 Jon Christensen, Pascale Anderle IGFBP6 (insulin-like growth factor binding protein 6) 15 Leon A Bach IL17A (interleukin 17A) 18 Norimitsu Inoue, Takashi Akazawa MAGEA3 (melanoma antigen family A, 3) 28 Biswajit Das, Sujit Suklabaidya, Sumeet Jain, Manas R Baisakh, Shantibhusan Senapati RRM2 (ribonucleotide reductase M2) 32 Ali Afrasiabi, Hamid Fiuji, Reza Mirhafez, Amir Avan YPEL3 (yippee-like 3 (Drosophila)) 38 Gizem Güpür, Mesut Muyan YPEL5 (yippee-like 5 (Drosophila)) 41 Gizem Güpür, Mesut Muyan PML (promyelocytic leukemia) 44 Andrea Rabellino, Pier Paolo Scaglioni SOCS6 (suppressor of cytokine signaling 6) 50 Julhash U Kazi, Amilcar Flores-Morales, Lars Rönnstrand

Leukaemia Section del(4)(q12q12) FIP1L1/PDGFRA 53 Adriana Zamecnikova, Soad Al Bahar t(5;9)(q14.1;p24) SSBP2/JAK2 59 Elizabeth A Morgan, Paola Dal Cin

Solid Tumour Section

Mesothelioma: t(14;22)(q32;q12) in mesothelioma 62 Ioannis Panagopoulos

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Deep Insight Section

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation 65 Federica Lo Sardo, Sabrina Strano, Giovanni Blandino

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Gene Section Short Communication

CXXC5 (CXXC finger protein 5) Pelin Yasar, Mesut Muyan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey (PY, MM)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/CXXC5ID52549ch5q31.html DOI: 10.4267/2042/55369 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Review on CXXC5, with data on DNA/RNA, on Description the protein encoded and where the gene is implicated. The gene is on the plus strand and encompasses 35 kb of DNA. Identity The exon number of gene is 3 and parts of the Other names: CF5, RINF, WID second and third exons encode the protein (ENSP00000302543). HGNC (Hugo): CXXC5 Transcription Location: 5q31.2 1447 bp long mRNA; 969 bp long open reading Local order: From centromere to telomere: frame. SPATA24-DNAJC18-ECSCR-TMEM173- UBE2D2-CXXC5 -PSD2-NRG2. Pseudogene Note: Orientation on forward strand. No reported pseudogenes.

Local order of CXXC5 is shown together with leading and subsequent genes on chromosome 5. The direction of arrows indicates transcriptional directions on the chromosome and arrow sizes approximate gene sizes.

Boxes are exons. The lines are introns. Shaded parts of the exon boxes are coding regions. Unshaded parts are noncoding regions.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 1 CXXC5 (CXXC finger protein 5) Yasar P, Muyan M

CXXC5 contains a nuclear localization signal adjacent to the CXXC-zinc finger domain.

Protein Implicated in Description Acute myeloid leukemia (AML) and CXXC5 encodes a 322 amino-acid protein with a Myelodysplastic syndrome (MDS) molecular mass of 33 kDa. Amino-acid sequence Disease suggests that CXXC5 contains a number of Acute myeloid leukemia (AML) is a disease phosphorylation and acetylation sites. manifested by cytogenetic anomalies affecting cell By homology, CXXC5 is considered to be a proliferation, death and differentiation (Renneville member of CXXC-type zinc finger protein family, et al., 2008). Myelodysplastic syndrome (MDS) which binds to non-methylated CpG dinuclotide defines a hematological condition with insufficient containing DNA. hematopoiesis. MDS results from chromosomal Expression deletions, inversions and translocations giving rise CXXC5 is expressed in various tissues. to trilineage dysplasia (Mhawech and Saleem, 2001). Localisation Oncogenesis CXXC5 protein is mainly in the nucleus. CXXC5 The region on the chromosome 5 which also protein may also be localized in the cytoplasm contains CXXC5 gene (5q31.2) is often deleted in coupled with Dishevelled (Dvl) protein (Andersson AML and MDS (Treppendahl et al., 2013). Low et al., 2009). survival rate has been observed in intensive Function chemotherapy treated patients with AML who show a high level of CXXC5 gene expression (Astori et CXXC5 can be induced by retinoid signaling and is al., 2013). required for myelopoiesis (Pendino et al., 2009). CXXC5 protein is involved in the DNA-damage Acute promyelocytic leukemia (APL) induced p53 activation as well as in the regulation Disease of cell cycle and apoptosis (Zhang et al., 2009). APL, which is characterized by the translocation CXXC5 protein participates in the TNF-a-induced event of the retinoic acid receptor alpha gene, is a apoptosis through association with SMAD (Wang rare subtype of AML in which leukemia cells are et al., 2013). sensitive to anthracyclines (Tallman and Altman, CXXC5 protein is a critical modulator of BMP4- 2008). regulated Wnt-signaling in neural stem cells (Andersson et al., 2009). Oncogenesis CXXC5 protein is shown to repress TET2 gene Terminal maturation of premyelocytic leukemia expression (Ko et al., 2013). cells requires the expression of CXXC5 (Pendino et Homology al., 2009). CXXC domain is a highly conserved domain of a Breast cancer class of proteins that interact with non-methylated Disease CpG dinucleotides (CpGs). The CXXC domain of Breast cancer is a disease which is mainly CXXC5 displays a significant homology to CXXC originated in the lining of the milk ducts and/or the domains of CXXC4 and TET3 proteins (Ko et al., lobules. 2013). Oncogenesis It has been shown that CXXC5 is transcriptionally Mutations upregulated in some solid tumors including Note melanoma, thyroid and breast cancer. In addition, Not defined yet. overexpression of CXXC5 in breast cancer is

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 2 CXXC5 (CXXC finger protein 5) Yasar P, Muyan M

suggested to be associated with poor prognosis Knappskog S, Myklebust LM, Busch C, Aloysius T, (Knappskog et al., 2011). Varhaug JE, Lønning PE, Lillehaug JR, Pendino F. RINF (CXXC5) is overexpressed in solid tumors and is an unfavorable prognostic factor in breast cancer. Ann Oncol. References 2011 Oct;22(10):2208-15 Mhawech P, Saleem A. Myelodysplastic syndrome: review Astori A, Fredly H, Aloysius TA, Bullinger L, Mansat-De of the cytogenetic and molecular data. Crit Rev Oncol Mas V, de la Grange P, Delhommeau F, Hagen KM, Hematol. 2001 Dec;40(3):229-38 Récher C, Dusanter-Fourt I, Knappskog S, Lillehaug JR, Pendino F, Bruserud Ø. CXXC5 (retinoid-inducible nuclear Tallman MS, Altman JK. Curative strategies in acute factor, RINF) is a potential therapeutic target in high-risk promyelocytic leukemia. Hematology Am Soc Hematol human acute myeloid leukemia. Oncotarget. 2013 Educ Program. 2008;:391-9 Sep;4(9):1438-48 Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Ko M, An J, Bandukwala HS, Chavez L, Aijö T, Pastor WA, Fenaux P, Preudhomme C. Cooperating gene mutations in Segal MF, Li H, Koh KP, Lähdesmäki H, Hogan PG, acute myeloid leukemia: a review of the literature. Aravind L, Rao A. Modulation of TET2 expression and 5- Leukemia. 2008 May;22(5):915-31 methylcytosine oxidation by the CXXC domain protein IDAX. Nature. 2013 May 2;497(7447):122-6 Andersson T, Södersten E, Duckworth JK, Cascante A, Fritz N, Sacchetti P, Cervenka I, Bryja V, Hermanson O. Treppendahl MB, Möllgård L, Hellström-Lindberg E, Cloos CXXC5 is a novel BMP4-regulated modulator of Wnt P, Grønbaek K. Downregulation but lack of promoter signaling in neural stem cells. J Biol Chem. 2009 Feb hypermethylation or somatic mutations of the potential 6;284(6):3672-81 tumor suppressor CXXC5 in MDS and AML with deletion 5q. Eur J Haematol. 2013 Mar;90(3):259-60 Pendino F, Nguyen E, Jonassen I, Dysvik B, Azouz A, Lanotte M, Ségal-Bendirdjian E, Lillehaug JR. Functional Wang X, Liao P, Fan X, Wan Y, Wang Y, Li Y, Jiang Z, Ye involvement of RINF, retinoid-inducible nuclear factor X, Mo X, Ocorr K, Deng Y, Wu X, Yuan W. CXXC5 (CXXC5), in normal and tumoral human myelopoiesis. Associates with Smads to Mediate TNF-α Induced Blood. 2009 Apr 2;113(14):3172-81 Apoptosis. Curr Mol Med. 2013 Sep;13(8):1385-96 ZHANG M, WANG R, WANG Y, DIAO F, LU F, GAO D, CHEN D, ZHAI Z, SHU H. The CXXC finger 5 protein is This article should be referenced as such: required for DNA damage-induced p53 activation. Sci Yasar P, Muyan M. CXXC5 (CXXC finger protein 5). Atlas China C Life Sci. 2009 Jun;52(6):528-38 Genet Cytogenet Oncol Haematol. 2015; 19(1):1-3.

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Gene Section Review

EIF4B (eukaryotic translation initiation factor 4B) Thomas Sbarrato, Emilie Horvilleur, Tuija Pöyry, Anne E Willis Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Rd, Leicester, LE1 9HN, UK (TS, EH, TP, AEW)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/EIF4BID53571ch12q13.html DOI: 10.4267/2042/55370 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract studied in detail. Review on eIF4B, with data on DNA/RNA, on the Protein protein encoded and where the gene is implicated. Description Identity eIF4B is a 79kDA protein composed of 611 residues. Many sites of phosphorylation have been Other names: EIF-4B, PRO1843 found for this protein using proteomics tools, HGNC (Hugo): EIF4B including 29 Ser, 13 Thr and 1 Tyr (Prasad et al., Location: 12q13.13 2009). Among them, two have been validated by further studies. The best studied phosphorylation DNA/RNA site is Ser422 by p70/S6kinase in response to mTOR pathway (Holz et al., 2005). Ser422 can also Description be phosphorylated by p90 (RSK) and PKB The eIF4B gene codes for EIF4B protein. eIF4B (Shahbazian et al., 2006; van Gorp et al., 2009). gene is 69.15 kb in length and is composed of 15 Ser406 phosphorylation is cell cycle dependent and exons (Figure 1). under control of mTOR and MAP kinase pathways (van Gorp et al., 2009). Ser406 is a target of Pim Transcription kinases (Yang et al., 2013). Finally, eIF4B is eIF4B mRNA is ubiquitously expressed, however, cleaved by caspase 3 after Asp45 during apoptosis regulation of eIF4B transcription has not been (Bushell et al., 2001) (Figure 2).

Figure 1: Schematic representation of eIF4B gene, which is composed of 15 exons shown in blue.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 4 EIF4B (eukaryotic translation initiation factor 4B) Sbarrato T, et al.

Figure 2: Schematic representation of eIF4B protein. The numbers refer to amino acids flanking the functional domains. Ser406 and Ser422 that can be phosphorylated by several kinases are indicated.

Figure 3: Initiation of translation.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 5 EIF4B (eukaryotic translation initiation factor 4B) Sbarrato T, et al.

Figure 4: Two possible models for eIF4B position in the initiation complex during scanning of 5'UTR.

Expression et al., 1999; Imataka et al., 1998; Lamphear et al., 1995; Wells et al., 1998). This complex will then The protein is reported to be expressed in most scan the untranslated region (UTR) of the mRNA tissues, excluding liver, smooth muscle or soft until a start codon is recognised (Kozak, 2002). tissues (Uhlen et al., 2010). Given the crucial role eIF4B acts at different levels to stimulate played by this protein in the cell, it is expected to be translation initiation: 1) by enhancing the ATPase expressed ubiquitously albeit probably to different and helicase activities of eIF4A and 2) by levels throughout different tissues. facilitating the recruitment of the 43S PIC. Localisation 1) Role of eIF4B in the stimulation of eIF4A eIF4B has a cytoplasmic localisation. Although the precise mechanisms of action of eIF4B on the enhanced helicase activity of eIF4F Function are not fully understood, knockdown/aberrant eIF4B is an RNA binding protein involved in the expression of eIF4B in mammalian cells led to the regulation of the initiation stage of protein reduction/stimulation in translation of mRNAs synthesis. This protein is critical for the recruitment containing highly structured 5'UTRs (Horvilleur et of the mRNA to the ribosome. It helps unwind al., 2013; Shahbazian et al., 2010). Additionally, secondary structures in the mRNA to allow the ATPase and helicase activity of free eIF4A was ribosome scanning, via enhancing both ATPase and shown to be significantly slower than the rates of helicase activities of eIF4A. translation initiation or the rates of scanning of the Translation of an mRNA initiates with the binding PIC (Grifo et al., 1984; Pause et al., 1994; Richter- of eukaryotic initiation factor complex eIF4F Cook et al., 1998). comprised of eIF4E, eIF4G and eIF4A (Pestova and Consequently, one can envisage that eIF4B can Kolupaeva, 2002) (Figure 3): help in the substrate (ATP and RNA) recognition - eIF4E interacts directly with the cap of the mRNA by eIF4A. As such, eIF4B can modulate the affinity and helps recruit the machinery to the 5'end of the for ATP and RNA by inducing conformational mRNA. changes in eIF4A (Bi et al., 2000; Marintchev et al., - eIF4G protein provides a scaffold, bridging 2009; Methot et al., 1994; Nielsen et al., 2011; interactions between eIF4A, eIF4E, eIF3, PABP Rogers Jr. et al., 2001; Rozovsky et al., 2008). and RNA. Additionally, eIF4B can enhance the efficiency of - Secondary structures in the mRNA that can be this process by coupling the ATP hydrolysis to detrimental to the binding/scanning of the ribosome duplex unwinding to avoid redundant, energy- are unwound by the helicase eIF4A and its consuming events (Ozes et al., 2011). In a manner cofactors eIF4B and eIF4H (Grifo et al., 1983; similar to other single-stranded DNA binding Lawson et al., 1989; Rozen et al., 1990). proteins that associate with helicases, one possible The binding of this eIF4F complex allows for the mode of action for eIF4B is to stabilize newly circularisation of the mRNA and the subsequent unwound single-stranded RNA. In support of this, a recruitment of the 43S pre-initiation complex (PIC) direct interaction between eIF4A and eIF4B in the composed of the small ribosomal subunit (40S), the presence of RNA and an ATP analog have been ternary complex (eIF2/met-tRNA/GTP) and several established via the C terminal region of eIF4B initiation factors (eIF1, eIF1A, eIF3 and eIF5) (Deo (Nielsen et al., 2011; Rozovsky et al., 2008).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 6 EIF4B (eukaryotic translation initiation factor 4B) Sbarrato T, et al.

Figure 5: mTOR and MEK/ERK/MAP kinase pathways converge on eIF4B.

2) Role of eIF4B in the recruitment of 43S PIC The spatial positioning of eIF4B on the scanning to mRNAs ribosome is poorly understood. The helicase Through its various domains, eIF4B is now known complex eIF4A/eIF4B could be located near the to promote the association of the various players in mRNA exit channel (i.e. 5'/behind the scanning the recruitment of the 43S PIC to the mRNA. The C PIC) or alternatively at the mRNA entry channel terminal RNA binding domain of eIF4B enables its (i.e. 3'/in front of the scanning PIC) (Figure 4). To binding to mRNA whereas the RRM motif triggers support the former hypothesis, a Brownian ratchet interaction with the rRNA from the 43S PIC model was proposed in which eIF4F is located near (Methot et al., 1996a; Naranda et al., 1994). The the exit channel of the PIC (Spirin, 2009). latter is thought to anchor the helicase eIF4A to the In this model, eIF4A-unwound and eIF4B-captured scanning ribosome (Methot et al., 1996a). single-stranded RNA would be scanned by Importantly, mammalian eIF4B dimerises and binds diffusion by the PIC. Contradictory, new evidence to eIF3a via its DRYG repeats, thus providing a have shown that yeast eIF4B mapped to the head of main link between the eIF4F-loaded mRNA and the the PIC near the entry channel (Walker et al., 43S PIC (Methot et al., 1996b). 2013). In such a case, the eIF4F complex would be These results provide evidence that eIF4B recruited to the cap and would be located at the participates in recruitment and assembly of the PIC forefront of the PIC, thus allowing efficient on mRNAs. Critically, recent findings have now unwinding and scanning (Marintchev et al., 2009). shown that interactions involving eIF4B via its New experimental approaches, including structures different domains are essential for the effective of the human ribosome associated with factors, assembly and efficient scanning of the 43S PIC. should be able to shed some light on the matter in Yeast eIF4B together with eIF4F and eIF3 the future. decreased the dependency on high concentrations of Homology eIF4A for the rapid assembly and recruitment of the 43S PIC on endogenous short leader mRNAs eIF4B is one of the least conserved initiation factors (Mitchell et al., 2010; Walker et al., 2013), thus in terms of sequence homology (Cheng and Gallie, eIF4B can mediate an enhancing effect on the PIC 2006), however, its function is conserved and recruitment to an mRNA. eIF4B homologues can be found across all

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 7 EIF4B (eukaryotic translation initiation factor 4B) Sbarrato T, et al.

eukaryotic species. In addition to the human eIF4B, frequent in NSCLC, where there can be either loss one of the most studied eIF4B homologs is the of heterozygocity or amplification, sometimes yeast protein, TIF3 (Altmann et al., 1993). eIF4H is coupled with unbalanced translocation. a 23kDa paralog of eIF4B showing homology to the eIF4B expression is significantly higher in NSCLC RRM RNA binding domain. eIF4H stimulates tumours showing this kind of alteration (Liang et eIF4A helicase activity in a similar way to eIF4B. al., 2013). Synergistic effect of mTOR and MEK inhibitors in Implicated in NSCLC cell lines is correlated with significant decrease in eIF4B phosphorylation (Zou et al., General role in cancer 2012). Note Oral squamous cell carcinoma eIF4B expression and phosphorylation are de- Note regulated in many cancers. In particular, Ser422 phosphorylation is at the crossroad of two major Activation of Laminin γ2 by eIF4B is found in pre- pathways in oncogenesis: MAP kinases and malignant oral dysplasia, where eIF4B is activated AKT/mTOR pathway (Shahbazian et al., 2006) by ERK/MAP kinase pathway (Degen et al., 2012). (Figure 5). In response to these signalling Laminin γ2 levels remain high in oral squamous pathways, eIF4B activates both global translation, cell carcinoma, although eIF4B has not been driving faster proliferation, and overexpression of studied in this context. specific oncoproteins such as MYC or BCL2 Prostatic cancer (Shahbazian et al., 2010). Activation of eIF4B and Note subsequent c-MYC induction is involved in arsenic- In Prostatic carcinoma, eIF4B phosphorylation by induced transformation in mouse epithelial cells Pim2 leads to resistance to apoptosis (Ren et al., (Zhang et al., 2011). Moreover, binding of 14-3-3 2013). sigma tumour suppressor to eIF4B in late mitosis regulates translation indicating direct involvement Lymphangioleiomyomatosis of eIF4B in regulation of cell cycle (Wilker et al., Note 2007). Finally, eIF4B is cleaved by a caspase eIF4B phosphorylation increased following dependent mechanism upon activation of tumour activation of mTOR pathway in necrosis factor pathway, suggesting a role in lymphangioleiomyomatosis (Gu et al., 2013). preventing apoptosis (Jeffrey et al., 2002). Diffuse large B-cell lymphoma Nasopharyngeal carcinoma (NPC) (DLBCL) Note Note Although not mutated, p53 is known to be up- eIF4B is up-regulated following activation of regulated in NPC. In a proteomic study, eIF4B was mTOR pathway in DLBCL and, in turn, activates shown to be down-regulated following p53 translation of proteins involved in DNA repair and knockdown in a NPC cell line (Sun et al., 2007). inhibition of apoptosis. T-cell lymphoblastic Elevated eIF4B level was shown to be poor leukemia/lymphoma prognosis in DLBCL (Horvilleur et al., 2013). Note Various cancers eIF4B mRNA was found to be up-regulated in a Note genome wide study comparing mouse model of Finally, amplification, duplication and deletion of thymic tumours (lymphoblastic leukaemia 12q13 have been described in different cancers precursor) to untransformed thymus (Lin and including sarcoma, glioma, bladder carcinoma or Aplan, 2007). anaplastic lymphoma without direct involvement of Gastric cancer eIF4B. Note To be noted A microarray study found eIF4B mRNA to be up- regulated in a panel of 22 patients after they became Doctors Thomas Sbarrato and Emilie Horvilleur resistant to combined cisplatin and fludarabine contributed equally to this work. treatment (Kim et al., 2011). Non-small cell lung cancer (NSCLC) References Note Grifo JA, Tahara SM, Morgan MA, Shatkin AJ, Merrick WC. New initiation factor activity required for globin mRNA Chromosomal aberrations in 12q13 region are translation. J Biol Chem. 1983 May 10;258(9):5804-10

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 8 EIF4B (eukaryotic translation initiation factor 4B) Sbarrato T, et al.

Grifo JA, Abramson RD, Satler CA, Merrick WC. RNA- Bushell M, Wood W, Carpenter G, Pain VM, Morley SJ, stimulated ATPase activity of eukaryotic initiation factors. J Clemens MJ. Disruption of the interaction of mammalian Biol Chem. 1984 Jul 10;259(13):8648-54 protein synthesis eukaryotic initiation factor 4B with the poly(A)-binding protein by caspase- and viral protease- Lawson TG, Lee KA, Maimone MM, Abramson RD, Dever mediated cleavages. J Biol Chem. 2001 Jun TE, Merrick WC, Thach RE. Dissociation of double- 29;276(26):23922-8 stranded polynucleotide helical structures by eukaryotic initiation factors, as revealed by a novel assay. Rogers GW Jr, Richter NJ, Lima WF, Merrick WC. Biochemistry. 1989 May 30;28(11):4729-34 Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. J Biol Chem. 2001 Aug Rozen F, Edery I, Meerovitch K, Dever TE, Merrick WC, 17;276(33):30914-22 Sonenberg N. Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol Cell Jeffrey IW, Bushell M, Tilleray VJ, Morley S, Clemens MJ. Biol. 1990 Mar;10(3):1134-44 Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor alpha family and Altmann M, Müller PP, Wittmer B, Ruchti F, Lanker S, a DNA-damaging agent for caspases and the double- Trachsel H. A Saccharomyces cerevisiae homologue of stranded RNA-dependent protein kinase. Cancer Res. mammalian translation initiation factor 4B contributes to 2002 Apr 15;62(8):2272-80 RNA helicase activity. EMBO J. 1993 Oct;12(10):3997- 4003 Kozak M. Pushing the limits of the scanning mechanism for initiation of translation. Gene. 2002 Oct 16;299(1-2):1- Méthot N, Pause A, Hershey JW, Sonenberg N. The 34 translation initiation factor eIF-4B contains an RNA-binding region that is distinct and independent from its Pestova TV, Kolupaeva VG. The roles of individual ribonucleoprotein consensus sequence. Mol Cell Biol. eukaryotic translation initiation factors in ribosomal 1994 Apr;14(4):2307-16 scanning and initiation codon selection. Genes Dev. 2002 Nov 15;16(22):2906-22 Naranda T, Strong WB, Menaya J, Fabbri BJ, Hershey JW. Two structural domains of initiation factor eIF-4B are Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 involved in binding to RNA. J Biol Chem. 1994 May mediate assembly of the translation preinitiation complex 20;269(20):14465-72 through dynamic protein interchange and ordered phosphorylation events. Cell. 2005 Nov 18;123(4):569-80 Pause A, Méthot N, Svitkin Y, Merrick WC, Sonenberg N. Dominant negative mutants of mammalian translation Cheng S, Gallie DR. Wheat eukaryotic initiation factor 4B initiation factor eIF-4A define a critical role for eIF-4F in organizes assembly of RNA and eIFiso4G, eIF4A, and cap-dependent and cap-independent initiation of poly(A)-binding protein. J Biol Chem. 2006 Aug translation. EMBO J. 1994 Mar 1;13(5):1205-15 25;281(34):24351-64 Lamphear BJ, Kirchweger R, Skern T, Rhoads RE. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Mapping of functional domains in eukaryotic protein Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N. synthesis initiation factor 4G (eIF4G) with picornaviral The mTOR/PI3K and MAPK pathways converge on eIF4B proteases. Implications for cap-dependent and cap- to control its phosphorylation and activity. EMBO J. 2006 independent translational initiation. J Biol Chem. 1995 Sep Jun 21;25(12):2781-91 15;270(37):21975-83 Lin YW, Aplan PD. Gene expression profiling of precursor Methot N, Pickett G, Keene JD, Sonenberg N. In vitro RNA T-cell lymphoblastic leukemia/lymphoma identifies selection identifies RNA ligands that specifically bind to oncogenic pathways that are potential therapeutic targets. eukaryotic translation initiation factor 4B: the role of the Leukemia. 2007 Jun;21(6):1276-84 RNA remotif. RNA. 1996a Jan;2(1):38-50 Sun Y, Yi H, Zhang PF, Li MY, Li C, Li F, Peng F, Feng Méthot N, Song MS, Sonenberg N. A region rich in XP, Yang YX, Yang F, Xiao ZQ, Chen ZC. Identification of aspartic acid, arginine, tyrosine, and glycine (DRYG) differential proteins in nasopharyngeal carcinoma cells with mediates eukaryotic initiation factor 4B (eIF4B) self- p53 silence by proteome analysis. FEBS Lett. 2007 Jan association and interaction with eIF3. Mol Cell Biol. 1996b 9;581(1):131-9 Oct;16(10):5328-34 Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen Imataka H, Gradi A, Sonenberg N. A newly identified N- CP, Reinhardt HC, Feng Y, Sharp PA, Sonenberg N, terminal amino acid sequence of human eIF4G binds White FM, Yaffe MB. 14-3-3sigma controls mitotic poly(A)-binding protein and functions in poly(A)-dependent translation to facilitate cytokinesis. Nature. 2007 Mar translation. EMBO J. 1998 Dec 15;17(24):7480-9 15;446(7133):329-32 Richter-Cook NJ, Dever TE, Hensold JO, Merrick WC. Rozovsky N, Butterworth AC, Moore MJ. Interactions Purification and characterization of a new eukaryotic between eIF4AI and its accessory factors eIF4B and protein translation factor. Eukaryotic initiation factor 4H. J eIF4H. RNA. 2008 Oct;14(10):2136-48 Biol Chem. 1998 Mar 27;273(13):7579-87 Marintchev A, Edmonds KA, Marintcheva B, Hendrickson Wells SE, Hillner PE, Vale RD, Sachs AB. Circularization E, Oberer M, Suzuki C, Herdy B, Sonenberg N, Wagner G. of mRNA by eukaryotic translation initiation factors. Mol Topology and regulation of the human eIF4A/4G/4H Cell. 1998 Jul;2(1):135-40 helicase complex in translation initiation. Cell. 2009 Feb 6;136(3):447-60 Deo RC, Bonanno JB, Sonenberg N, Burley SK. Recognition of polyadenylate RNA by the poly(A)-binding Prasad TS, Kandasamy K, Pandey A. Human Protein protein. Cell. 1999 Sep 17;98(6):835-45 Reference Database and Human Proteinpedia as discovery tools for systems biology. Methods Mol Biol. Bi X, Ren J, Goss DJ. Wheat germ translation initiation 2009;577:67-79 factor eIF4B affects eIF4A and eIFiso4F helicase activity by increasing the ATP binding affinity of eIF4A. Spirin AS. How does a scanning ribosomal particle move Biochemistry. 2000 May 16;39(19):5758-65 along the 5'-untranslated region of eukaryotic mRNA?

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Brownian Ratchet model. Biochemistry. 2009 Nov hyperactivation and dysregulated laminin γ2 expression in 17;48(45):10688-92 oral dysplasia and squamous cell carcinoma. Am J Pathol. 2012 Jun;180(6):2462-78 van Gorp AG, van der Vos KE, Brenkman AB, Bremer A, van den Broek N, Zwartkruis F, Hershey JW, Burgering Zou ZQ, Zhang LN, Wang F, Bellenger J, Shen YZ, Zhang BM, Calkhoven CF, Coffer PJ. AGC kinases regulate XH. The novel dual PI3K/mTOR inhibitor GDC-0941 phosphorylation and activation of eukaryotic translation synergizes with the MEK inhibitor U0126 in non-small cell initiation factor 4B. Oncogene. 2009 Jan 8;28(1):95-106 lung cancer cells. Mol Med Rep. 2012 Feb;5(2):503-8 Mitchell SF, Walker SE, Algire MA, Park EH, Hinnebusch Gu X, Yu JJ, Ilter D, Blenis N, Henske EP, Blenis J. AG, Lorsch JR. The 5'-7-methylguanosine cap on Integration of mTOR and estrogen-ERK2 signaling in eukaryotic mRNAs serves both to stimulate canonical lymphangioleiomyomatosis pathogenesis. Proc Natl Acad translation initiation and to block an alternative pathway. Sci U S A. 2013 Sep 10;110(37):14960-5 Mol Cell. 2010 Sep 24;39(6):950-62 Liang Y, Liu M, Wang P, Ding X, Cao Y. Analysis of 20 Shahbazian D, Parsyan A, Petroulakis E, Topisirovic I, genes at chromosome band 12q13: RACGAP1 and Martineau Y, Gibbs BF, Svitkin Y, Sonenberg N. Control of MCRS1 overexpression in nonsmall-cell lung cancer. cell survival and proliferation by mammalian eukaryotic Genes Chromosomes Cancer. 2013 Mar;52(3):305-15 initiation factor 4B. Mol Cell Biol. 2010 Mar;30(6):1478-85 Ren K, Gou X, Xiao M, Wang M, Liu C, Tang Z, He W. The Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson over-expression of Pim-2 promote the tumorigenesis of K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, prostatic carcinoma through phosphorylating eIF4B. Wernerus H, Björling L, Ponten F. Towards a knowledge- Prostate. 2013 Sep;73(13):1462-9 based Human Protein Atlas. Nat Biotechnol. 2010 Dec;28(12):1248-50 Walker SE, Zhou F, Mitchell SF, Larson VS, Valasek L, Hinnebusch AG, Lorsch JR. Yeast eIF4B binds to the head Kim HK, Choi IJ, Kim CG, Kim HS, Oshima A, Michalowski of the 40S ribosomal subunit and promotes mRNA A, Green JE. A gene expression signature of acquired recruitment through its N-terminal and internal repeat chemoresistance to cisplatin and fluorouracil combination domains. RNA. 2013 Feb;19(2):191-207 chemotherapy in gastric cancer patients. PLoS One. 2011 Feb 18;6(2):e16694 Yang J, Wang J, Chen K, Guo G, Xi R, Rothman PB, Whitten D, Zhang L, Huang S, Chen JL. eIF4B Nielsen KH, Behrens MA, He Y, Oliveira CL, Jensen LS, phosphorylation by pim kinases plays a critical role in Hoffmann SV, Pedersen JS, Andersen GR. Synergistic cellular transformation by Abl oncogenes. Cancer Res. activation of eIF4A by eIF4B and eIF4G. Nucleic Acids 2013 Aug 1;73(15):4898-908 Res. 2011 Apr;39(7):2678-89 Horvilleur E, Sbarrato T, Hill K, Spriggs RV, Screen M, Öze ş AR, Feoktistova K, Avanzino BC, Fraser CS. Duplex Goodrem PJ, Sawicka K, Chaplin LC, Touriol C, Packham unwinding and ATPase activities of the DEAD-box helicase G, Potter KN, Dirnhofer S, Tzankov A, Dyer MJ, Bushell M, eIF4A are coupled by eIF4G and eIF4B. J Mol Biol. 2011 MacFarlane M, Willis AE. A role for eukaryotic initiation Sep 30;412(4):674-87 factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma. Leukemia. 2014 May;28(5):1092- Zhang Y, Wang Q, Guo X, Miller R, Guo Y, Yang HS. 102 Activation and up-regulation of translation initiation factor 4B contribute to arsenic-induced transformation. Mol This article should be referenced as such: Carcinog. 2011 Jul;50(7):528-38 Sbarrato T, Horvilleur E, Pöyry T, Willis AE. EIF4B Degen M, Natarajan E, Barron P, Widlund HR, Rheinwald (eukaryotic translation initiation factor 4B). Atlas Genet JG. MAPK/ERK-dependent translation factor Cytogenet Oncol Haematol. 2015; 19(1):4-10.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 10

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Gene Section Review

FOXQ1 (forkhead box Q1) Jon Christensen, Pascale Anderle Institute for Macromolecular Chemistry, Alber-Ludwigs-University of Freiburg, Freiburg, Germany (JC), Swiss Institute of Bioinformatics, Lausanne, Switzerland (PA)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/FOXQ1ID45906ch6p25.html DOI: 10.4267/2042/55371 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

is a member of the Forkhead box (Fox) Abstract superfamily. Review on FOXQ1, with data on DNA/RNA, on the protein encoded and where the gene is implicated. Identity Other names: HFH1 HGNC (Hugo): FOXQ1 Location: 6p25.3 DNA/RNA Description The FOXQ1 gene is 2338 base pairs in length and is intronless. Transcription Figure 1. Structure of the winged helix domain. α- helices are shown as red cylinders (H1, H2 and H3), β- In mouse Foxq1 has been reported to be regulated strands as blue arrows and W1 and W2 denote the wings by Hoxa1 (Martinez-Ceballos et al., 2005), Hoxc13 (Clark et al., 1993; Gajiwala and Burley, 2000). (Potter et al., 2006) and Tgf β (Zhang et al., 2011). In human FOXQ1 has been shown to be a target of The family members share a conserved DNA- the Wnt pathway (Christensen et al., 2013; Xia et binding domain named forkhead box or winged al., 2014). helix domain. The domain consists of three a-helices, three β- Protein sheets and two loops termed wings. Description Expression The forkhead box Q1 gene codes for a 403 amino Predominantly in the stomach, trachea, bladder and acid long protein with a size of 41.5 kDa. FOXQ1 salivary gland (Bieller et al., 2001).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 11 FOXQ1 (forkhead box Q1) Christensen J, Anderle P

Figure 2. Graphical illustration of the FOXQ1 amino acid sequence and domains. (I) Acid and serine-rich domain. (WH) winged helix domain. (II) Serin-rich domain. (III) Proline-rich domain. (IV) Functional conserved domain (Hong et al., 2001; Wu et al., 2013).

Function Breast cancer In mice Foxq1 is involved in hair follicle Prognosis differentiation (Hong et al., 2001; Potter et al., FOXQ1 expression in breast cancer patients is 2006). associated with poor survival, high grade, A mutation in the Foxq1 gene is responsible for an metastatic status and basal-like phenotype (Qiao et impaired differentiation of the hair shaft in the satin al., 2011). mice (Hong et al., 2001). In the digestive system Oncogenesis Foxq1 has been shown to regulate acid secretion FOXQ1 overexpression was observed in invasive and expression of Muc5ac (Goering et al., 2008; breast cancer cell lines compared to non-invasive. Verzi et al., 2008). FOXQ1 expression increases breast cancer cell Homology proliferation, migration and invasion in vitro and According to NCBI the following genes have been metastasis in vivo (Zhang et al., 2011). FOXQ1 suggested to be putative homologues: FOXQ1 (H. promotes an EMT phenotype through sapiens), Foxq1 (M. musculus), Foxq1 (R. transcriptional regulation of CDH1 (Qiao et al., norvegicus), Foxq1a (D. rerio) and Foxq1b (D. 2011; Zhang et al., 2011). rerio). Conserved domains from CDD found in Colorectal cancer protein sequences by rpsblast searching was FH (cl00061). Oncogenesis Several studies have shown FOXQ1 to be Mutations overexpressed in colorectal tumor samples compared to healthy colonocytes (Bieller et al., Note 2001; Sabates-Bellver et al., 2007; Kaneda et al., Mutations in the Foxq1 gene is responsible for the 2010; Christensen et al., 2013). hair follicle defects seen in the satin mouse mutant. The increased expression of FOXQ1 could be due Three mutations have been described leading to to a hyperactive Wnt pathway in these tumors. Wnt similar phenotypes of the animals. Foxq1 sa has a 67 activity directly correlates with FOXQ1 expression bp deletion from 686-752 and a base pair change in colorectal cancer cell lines and β-catenin can CA-AT at position 766-767. Foxq1 sa-el has a point bind to the promoter of FOXQ1 and increase mutation a position 383 changing T to G thus transcription (Christensen et al., 2013). FOXQ1 replacing isoleucine with serin at position 128 in expression can induce an EMT phenotype (Qiao et the protein. Foxq1 sa-J has C to T mutation in al., 2011; Abba et al., 2013). FOXQ1 does not position 490 changing the amino acide arginine to increase growth but seems to protect from apoptosis cysteine at position 164 in the protein (Hong et al., (Kaneda et al., 2010; Qiao et al., 2011; Abba et al., 2001; Wu et al., 2013). 2013). The anti-apoptotic effect was mediated through FOXQ1 regulation of p21 (Kaneda et al., Implicated in 2010). Bladder cancer Gastric cancer Oncogenesis Prognosis FOXQ1 was overexpressed in bladder cancer The expression of FOXQ1 was a prognostic factor samples. Depletion of FOXQ1 expression in for overall survival and correlated with tumor size, bladder cancer cell lines reduced invasiveness and grade and tumor-node metastasis stage (Liang et al., EMT markers (Zhu et al., 2013). 2013).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 12 FOXQ1 (forkhead box Q1) Christensen J, Anderle P

Oncogenesis Potter CS, Peterson RL, Barth JL, Pruett ND, Jacobs DF, Kern MJ, Argraves WS, Sundberg JP, Awgulewitsch A. FOXQ1 increases migration and proliferation by Evidence that the satin hair mutant gene Foxq1 is among downregulating NRXN3. multiple and functionally diverse regulatory targets for Hoxc13 during hair follicle differentiation. J Biol Chem. Glioma 2006 Sep 29;281(39):29245-55 Disease Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo Tumors that arise from the glial cells, the most E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki common site is the brain. JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A, Faggiani R, Anti M, Jiricny J, Clevers H, Marra G. Oncogenesis Transcriptome profile of human colorectal adenomas. Mol FOXQ1 increased migration and proliferation by Cancer Res. 2007 Dec;5(12):1263-75 downregulating NRXN3 (Sun et al., 2013). Goering W, Adham IM, Pasche B, Manner J, Ochs M, Engel W, Zoll B. Impairment of gastric acid secretion and Hepatocarcinoma increase of embryonic lethality in Foxq1-deficient mice. Cytogenetics Cytogenet Genome Res. 2008;121(2):88-95 FOXQ1 correlated with overall worse survival and Verzi MP, Khan AH, Ito S, Shivdasani RA. Transcription higher recurrence (Wang et al., 2013; Xia et al., factor foxq1 controls mucin gene expression and granule 2014). content in mouse stomach surface mucous cells. Gastroenterology. 2008 Aug;135(2):591-600 Oncogenesis Kaneda H, Arao T, Tanaka K, Tamura D, Aomatsu K, In hepatocarcinoma FOXQ1 directly activated the Kudo K, Sakai K, De Velasco MA, Matsumoto K, Fujita Y, EMT transcription factor ZEB2. This led to an Yamada Y, Tsurutani J, Okamoto I, Nakagawa K, Nishio K. EMT phenotype and increased lung metastasis. FOXQ1 is overexpressed in colorectal cancer and FOXQ1 and ZEB2 expression correlated positively enhances tumorigenicity and tumor growth. Cancer Res. in hepatocarcinoma samples but inversely with 2010 Mar 1;70(5):2053-63 CDH1. FOXQ1 induced metastasis through Feuerborn A, Srivastava PK, Küffer S, Grandy WA, regulation of VersicanV1, which promoted tumor- Sijmonsma TP, Gretz N, Brors B, Gröne HJ. The Forkhead factor FoxQ1 influences epithelial differentiation. J Cell associated-macrophages attraction. Also, similarly Physiol. 2011 Mar;226(3):710-9 to colorectal cancer expression of FOXQ1 was Qiao Y, Jiang X, Lee ST, Karuturi RK, Hooi SC, Yu Q. regulated by the Wnt pathway in hepatocarcinoma FOXQ1 regulates epithelial-mesenchymal transition in (Xia et al., 2014). human cancers. Cancer Res. 2011 Apr 15;71(8):3076-86 Non-small-cell lung carcinoma Zhang H, Meng F, Liu G, Zhang B, Zhu J, Wu F, Ethier SP, Miller F, Wu G. Forkhead transcription factor foxq1 Prognosis promotes epithelial-mesenchymal transition and breast FOXQ1 expression was associated with poor cancer metastasis. Cancer Res. 2011 Feb 15;71(4):1292- prognosis and EMT (Feng et al., 2012). 301 Ovarian cancer Feng J, Zhang X, Zhu H, Wang X, Ni S, Huang J. FoxQ1 overexpression influences poor prognosis in non-small cell Oncogenesis lung cancer, associates with the phenomenon of EMT. FOXQ1 expression increased ovarian cancer cell PLoS One. 2012;7(6):e39937 proliferation, invasion and induced an EMT Gao M, Shih IeM, Wang TL. The role of forkhead box q1 phenotype (Gao et al., 2012). transcription factor in ovarian epithelial carcinomas. Int J Mol Sci. 2012 Oct 26;13(11):13881-93 References Abba M, Patil N, Rasheed K, Nelson LD, Mudduluru G, Leupold JH, Allgayer H. Unraveling the role of FOXQ1 in Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure colorectal cancer metastasis. Mol Cancer Res. 2013 of the HNF-3/fork head DNA-recognition motif resembles Sep;11(9):1017-28 histone H5. Nature. 1993 Jul 29;364(6436):412-20 Christensen J, Bentz S, Sengstag T, Shastri VP, Anderle Gajiwala KS, Burley SK. Winged helix proteins. Curr Opin P. FOXQ1, a novel target of the Wnt pathway and a new Struct Biol. 2000 Feb;10(1):110-6 marker for activation of Wnt signaling in solid tumors. PLoS One. 2013;8(3):e60051 Bieller A, Pasche B, Frank S, Gläser B, Kunz J, Witt K, Zoll B. Isolation and characterization of the human forkhead Liang SH, Yan XZ, Wang BL, Jin HF, Yao LP, Li YN, Chen gene FOXQ1. DNA Cell Biol. 2001 Sep;20(9):555-61 M, Nie YZ, Wang X, Guo XG, Wu KC, Ding J, Fan DM. Increased expression of FOXQ1 is a prognostic marker for Hong HK, Noveroske JK, Headon DJ, Liu T, Sy MS, patients with gastric cancer. Tumour Biol. 2013 Justice MJ, Chakravarti A. The winged helix/forkhead Oct;34(5):2605-9 transcription factor Foxq1 regulates differentiation of hair in satin mice. Genesis. 2001 Apr;29(4):163-71 Sun HT, Cheng SX, Tu Y, Li XH, Zhang S. FoxQ1 promotes glioma cells proliferation and migration by Martinez-Ceballos E, Chambon P, Gudas LJ. Differences regulating NRXN3 expression. PLoS One. in gene expression between wild type and Hoxa1 knockout 2013;8(1):e55693 embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal. J Biol Chem. 2005 Wang W, He S, Ji J, Huang J, Zhang S, Zhang Y. The Apr 22;280(16):16484-98 prognostic significance of FOXQ1 oncogene

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 13 FOXQ1 (forkhead box Q1) Christensen J, Anderle P

overexpression in human hepatocellular carcinoma. Pathol Apr;42(4):1271-8 Res Pract. 2013 Jun;209(6):353-8 Xia L, Huang W, Tian D, Zhang L, Qi X, Chen Z, Shang X, Wu B, Herbert Pratt C, Potter CS, Silva KA, Kennedy V, Nie Y, Wu K. Forkhead box Q1 promotes hepatocellular Sundberg JP. R164C mutation in FOXQ1 H3 domain carcinoma metastasis by transactivating ZEB2 and affects formation of the hair medulla. Exp Dermatol. 2013 VersicanV1 expression. Hepatology. 2014 Mar;59(3):958- Mar;22(3):234-6 73

Zhu Z, Zhu Z, Pang Z, Xing Y, Wan F, Lan D, Wang H. This article should be referenced as such: Short hairpin RNA targeting FOXQ1 inhibits invasion and metastasis via the reversal of epithelial-mesenchymal Christensen J, Anderle P. FOXQ1 (forkhead box Q1). Atlas transition in bladder cancer. Int J Oncol. 2013 Genet Cytogenet Oncol Haematol. 2015; 19(1):11-14.

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Gene Section Short Communication

IGFBP6 (insulin-like growth factor binding protein 6) Leon A Bach Department of Endocrinology and Diabetes, Alfred Hospital and Department of Medicine (Alfred), Monash University, Melbourne 3004, Australia (LAB)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/IGFBP6ID40933ch12q13.html DOI: 10.4267/2042/55372 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review on IGFBP6, with data on DNA/RNA, on the protein encoded and where the gene is implicated. Identity Other names: IBP6 HGNC (Hugo): IGFBP6 Location: 12q13.13 DNA/RNA Description The size of the IGFBP6 gene is 4.91 kb and it Structure of the C-terminal domain of human IGFBP-6 (Headey et al., 2004; Bach et al., 2013). contains 4 exons (Thierry-Mieg and Thierry-Mieg, 2006). It consists of 3 domains: the N- and C-terminal Transcription domains, which contain internal disulfide bonds, are joined by a linker domain. It contains 8 One 1175 bp transcript encodes the full-sized 240 disulfide bonds, 5 in the N-terminal IGFBP domain amino acid protein. and 3 in the C-terminal domain (Neumann et al., Smaller transcripts sized 597, 705 and 463 bp may 1998; Neumann and Bach, 1999). Of these, the first be incomplete and putatively encode fragments 3 N-terminal disulfides are unique, whereas the containing 51-140 amino acids (Thierry-Mieg and remaining 2 N-terminal and 3 C-terminal disulfides Thierry-Mieg, 2006). are homologous with other IGFBPs. A peptide based on the N-terminal subdomain is largely Protein unstructured (Chandrashekaran et al., 2007), whereas the IGF binding subdomain is conserved Description with other IGFBPs. Human IGFBP-6 is O- IGFBP-6 belongs to the insulin-like growth factor glycosylated on 5 Ser/Thr residues within the linker binding protein family. domain, which has a distinct sequence from other It is expressed as a 240 amino acid proprotein, and IGFBPs (Bach et al., 1992; Neumann et al., 1998). processed to a 213-216 amino acid mature protein. The C-terminal domain contains a thyroglobulin

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 15 IGFBP6 (insulin-like growth factor binding protein 6) Bach LA

type 1 fold (Headey et al., 2004), which is also true other proteins containing a thyroglobulin type 1 for other IGFBPs, and a functional nuclear fold. localization sequence (Iosef et al., 2008). IGFBP-6 is found in mammalian species including Expression man, cow, rat and mouse, as well as trout and salmon. The IGFBP6 gene is duplicated in IGFBP6 is widely expressed in human tissues, with zebrafish, and each gene has a distinct expression low levels of transcripts found in most tissues. pattern; however, overexpression of either gene Expression is highest in smooth muscle, olfactory inhibits embryonic growth and development (Wang bulb, ganglia, retina and the atrioventricular node et al., 2009). (Wu et al., 2013). IGFBP6 is also found in many body fluids, including serum, cerebrospinal fluid, Implicated in amniotic fluid, and follicular fluid (Baxter and Saunders, 1992; Bach, 1999; Kolker et al., 2012). Various cancers IGFBP6 expression is regulated in a cell-specific Note manner by cAMP, IGFs, retinoic acid, vitamin D, In many studies, IGFBP-6 expression is lower in glucocorticoids, p53, beta-catenin, hedgehog, TGF- (1) malignant vs normal cells; and (2) metastatic vs beta and SEMA3B (Bach et al., 2013). primary tumors, suggesting that it has an inhibitory Localisation effect on tumor development, at least in part by Predominantly extracellular. Nuclear localization inhibiting IGF actions. Examples include via a C-domain nuclear localization signal that rhabdomyosarcoma, head and neck cancer, lung binds importin-a has also been reported (Iosef et al., cancer and gastric cancer (Bach et al., 2013). 2008). Exogenously added or overexpressed IGFBP-6 inhibits rhabdomyosarcoma and neuroblastoma Function xenograft growth in mice (Grellier et al., 1998; Unlike other IGFBPs, IGFBP-6 has a ~50-fold Gallicchio et al., 2001). IGFBP6 has been binding preference for IGF-II over IGF-I. It implicated as a tumor suppressor in nasopharyngeal therefore is a relatively specific inhibitor of IGF-II cancer by its role as a transcription factor for EGR- actions (Bach, 1999; Bach, 2005; Bach et al., 1 (Kuo et al., 2010). 2013). It is antiproliferative and proapoptotic in a number of cell lines in vitro (Bach, 1999; Bach, Chronic renal failure 2005; Bach et al., 2013). At least some of its Note actions in regulating cell fate are mediated by Circulating IGFBP-6 levels are increased in patients interaction with Ku80, a DNA-end binding protein with chronic renal failure (Powell et al., 1997; Van (Iosef et al., 2010). IGFBP-6 has also been reported Doorn et al., 1999) and this, together with increased to have IGF-independent actions, such as levels of other IGFBPs, may contribute to impaired promotion of cancer cell migration an IGF- IGF action in these patients. independent mechanism that involves binding Proliferative vitreoretinopathy prohibitin-2 (Fu et al., 2007; Fu et al., 2013) and angiogenesis (Zhang et al., 2012). It has been Note reported to be a tumor suppressor in IGFBP-6 levels are increased in serum and vitreous nasopharyngeal cancer through regulation of EGR- from patients with this condition, and serum levels 1 expression (Kuo et al., 2010). decreased after vitrectomy (Yu et al., 2014). As well as binding IGFs with high affinity, IGFBP- Non islet-cell tumor hypoglycemia 6 also binds other unrelated proteins, including importin-α, prohibitin-2 and Ku80 as described Note above. Other proteins that bind IGFBP-6 inhibits This rare condition is due to overexpression by osteoblast differentiation, which may be mediated tumors of a partially processed form of IGF-II that by binding to LIM mineralization protein-1 (LMP- does not form normal serum complexes with 1) (Strohbach et al., 2008), the vitamin D receptor IGFBPs and the acid-labile subunit and therefore (Cui et al., 2011), and the thyroid hormone-α has increased bioavailability. IGFBP-6 levels are receptor (Qiu et al., 2012). increased in this condition (Van Doorn et al., 1999). Global deletion of IGFBP6 expression does not result in a major phenotype, presumable because of References functional redundancy with other IGFBPs. Bach LA, Thotakura NR, Rechler MM. Human insulin-like growth factor binding protein-6 is O-glycosylated. Biochem Homology Biophys Res Commun. 1992 Jul 15;186(1):301-7 IGFBP-6 shares homology with IGFBPs 1-5 in its Baxter RC, Saunders H. Radioimmunoassay of insulin-like N-terminal IGF binding domain and its C-terminal growth factor-binding protein-6 in human serum and other domain. It shares homology in its C-domain with body fluids. J Endocrinol. 1992 Jul;134(1):133-9

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 16 IGFBP6 (insulin-like growth factor binding protein 6) Bach LA

Powell DR, Liu F, Baker BK, Hintz RL, Durham SK, Brewer Strohbach C, Kleinman S, Linkhart T, Amaar Y, Chen ST, ED, Frane JW, Tonshoff B, Mehls O, Wingen AM, Watkins Mohan S, Strong D. Potential involvement of the SL, Hogg RJ, Lee PD. Insulin-like growth factor-binding interaction between insulin-like growth factor binding protein-6 levels are elevated in serum of children with protein (IGFBP)-6 and LIM mineralization protein (LMP)-1 chronic renal failure: a report of the Southwest Pediatric in regulating osteoblast differentiation. J Cell Biochem. Nephrology Study Group. J Clin Endocrinol Metab. 1997 2008 Aug 1;104(5):1890-905 Sep;82(9):2978-84 Wang X, Lu L, Li Y, Li M, Chen C, Feng Q, Zhang C, Duan Grellier P, De Galle B, Babajko S. Expression of insulin- C. Molecular and functional characterization of two distinct like growth factor-binding protein 6 complementary DNA IGF binding protein-6 genes in zebrafish. Am J Physiol alters neuroblastoma cell growth. Cancer Res. 1998 Apr Regul Integr Comp Physiol. 2009 May;296(5):R1348-57 15;58(8):1670-6 Iosef C, Vilk G, Gkourasas T, Lee KJ, Chen BP, Fu P, Neumann GM, Marinaro JA, Bach LA. Identification of O- Bach LA, Lajoie G, Gupta MB, Li SS, Han VK. Insulin-like glycosylation sites and partial characterization of growth factor binding protein-6 (IGFBP-6) interacts with carbohydrate structure and disulfide linkages of human DNA-end binding protein Ku80 to regulate cell fate. Cell insulin-like growth factor binding protein 6. Biochemistry. Signal. 2010 Jul;22(7):1033-43 1998 May 5;37(18):6572-85 Kuo YS, Tang YB, Lu TY, Wu HC, Lin CT. IGFBP-6 plays Bach LA. Insulin-like growth factor binding protein-6: the a role as an oncosuppressor gene in NPC pathogenesis "forgotten" binding protein? Horm Metab Res. 1999 Feb- through regulating EGR-1 expression. J Pathol. 2010 Mar;31(2-3):226-34 Nov;222(3):299-309 Neumann GM, Bach LA. The N-terminal disulfide linkages Cui J, Ma C, Qiu J, Ma X, Wang X, Chen H, Huang B. A of human insulin-like growth factor-binding protein-6 novel interaction between insulin-like growth factor binding (hIGFBP-6) and hIGFBP-1 are different as determined by protein-6 and the vitamin D receptor inhibits the role of mass spectrometry. J Biol Chem. 1999 May vitamin D3 in osteoblast differentiation. Mol Cell 21;274(21):14587-94 Endocrinol. 2011 May 16;338(1-2):84-92 Van Doorn J, Ringeling AM, Shmueli SS, Kuijpers MC, Kolker E, Higdon R, Haynes W, Welch D, Broomall W, Hokken-Koelega AC, van Buul-Offers SC, Jansen M. Lancet D, Stanberry L, Kolker N. MOPED: Model Circulating levels of human insulin-like growth factor Organism Protein Expression Database. Nucleic Acids binding protein-6 (IGFBP-6) in health and disease as Res. 2012 Jan;40(Database issue):D1093-9 determined by radioimmunoassay. Clin Endocrinol (Oxf). 1999 May;50(5):601-9 Qiu J, Ma XL, Wang X, Chen H, Huang BR. Insulin-like growth factor binding protein-6 interacts with the thyroid Gallicchio MA, Kneen M, Hall C, Scott AM, Bach LA. hormone receptor α1 and modulates the thyroid hormone- Overexpression of insulin-like growth factor binding response in osteoblastic differentiation. Mol Cell Biochem. protein-6 inhibits rhabdomyosarcoma growth in vivo. Int J 2012 Feb;361(1-2):197-208 Cancer. 2001 Dec 1;94(5):645-51 Zhang C, Lu L, Li Y, Wang X, Zhou J, Liu Y, Fu P, Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P, Gallicchio MA, Bach LA, Duan C. IGF binding protein-6 Bach LA, Norton RS. C-terminal domain of insulin-like expression in vascular endothelial cells is induced by growth factor (IGF) binding protein-6: structure and hypoxia and plays a negative role in tumor angiogenesis. interaction with IGF-II. Mol Endocrinol. 2004 Int J Cancer. 2012 May 1;130(9):2003-12 Nov;18(11):2740-50 Bach LA, Fu P, Yang Z. Insulin-like growth factor-binding Bach LA. IGFBP-6 five years on; not so 'forgotten'? Growth protein-6 and cancer. Clin Sci (Lond). 2013 Horm IGF Res. 2005 Jun;15(3):185-92 Feb;124(4):215-29 Thierry-Mieg D, Thierry-Mieg J. AceView: a Fu P, Yang Z, Bach LA. Prohibitin-2 binding modulates comprehensive cDNA-supported gene and transcripts insulin-like growth factor-binding protein-6 (IGFBP-6)- annotation. Genome Biol. 2006;7 Suppl 1:S12.1-14 induced rhabdomyosarcoma cell migration. J Biol Chem. 2013 Oct 11;288(41):29890-900 Chandrashekaran IR, Yao S, Wang CC, Bansal PS, Alewood PF, Forbes BE, Wallace JC, Bach LA, Norton RS. Wu C, Macleod I, Su AI. BioGPS and MyGene.info: The N-terminal subdomain of insulin-like growth factor organizing online, gene-centric information. Nucleic Acids (IGF) binding protein 6. Structure and interaction with Res. 2013 Jan;41(Database issue):D561-5 IGFs. Biochemistry. 2007 Mar 20;46(11):3065-74 Yu J, Peng R, Chen H, Cui C, Ba J, Wang F. Kininogen 1 Fu P, Thompson JA, Bach LA. Promotion of cancer cell and insulin-like growth factor binding protein 6: candidate migration: an insulin-like growth factor (IGF)-independent serum biomarkers of proliferative vitreoretinopathy. Clin action of IGF-binding protein-6. J Biol Chem. 2007 Aug Exp Optom. 2014 Jan;97(1):72-9 3;282(31):22298-306 This article should be referenced as such: Iosef C, Gkourasas T, Jia CY, Li SS, Han VK. A functional nuclear localization signal in insulin-like growth factor Bach LA. IGFBP6 (insulin-like growth factor binding protein binding protein-6 mediates its nuclear import. 6). Atlas Genet Cytogenet Oncol Haematol. 2015; Endocrinology. 2008 Mar;149(3):1214-26 19(1):15-17.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 17

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Review

IL17A (interleukin 17A) Norimitsu Inoue, Takashi Akazawa Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan (NI, TA)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/IL17AID40945ch6p12.html DOI: 10.4267/2042/55373 This article is an update of : Inoue N, Akazawa T. IL17A (interleukin 17A). Atlas Genet Cytogenet Oncol Haematol 2011;15(8):662-666.

Abstract hepatic diseases 1) - MIR206 (microRNA 206) - MIR133B (microRNA 133b) - IL17A - IL17F Interleukin-17A (IL17A), a characteristic cytokine (interleukin 17F) - SLC25A20P1 (solute carrier produced by the T helper 17 cells (Th17 cells), can family 25, member 20 pseudogene 1) - MCM3 form either a homodimer or a heterodimer with (minichromosome maintenance complex IL17F. component 3) - centromere. It is produced not only by Th17 cells, but also by cytotoxic CD8 + T cells (Tc17 cells), γδ T cells, DNA/RNA invariant natural killer T cells (iNKT cells), lymphoid tissue inducer cells (LTi cells), and other Note hematopoietic and non-hematopoietic cells. During IL17A was initially identified in a subtractive development, these cells exhibit flexible or plastic hybridization screen of a rodent T cell library as features distinct from those of Th1 and Th2 cells. mouse cytotoxic T lymphocyte-associated antigen 8 IL17A plays important roles in the pathogenesis of (mCTLA8) (Rouvier et al., 1993), but is now autoimmune diseases and in the host defenses recognized as a characteristic cytokine of the Th17 against bacterial and fungal infections. cell subset, which has effector functions distinct Expression of IL17A and its related factors, as well from those of Th1 and Th2 cells (Korn et al., 2009; as the infiltration of IL17A-producing cells into the Kurebayashi et al., 2013). tumor microenvironment, has been implicated in Description anti-tumor or pro-tumor effects in various cancers. The IL17A gene spans a region of 4252 bp, Keywords: Th17 cells, ROR γt, STAT3, IL23, consisting of three exons. TGF β, inflammation Transcription Identity The transcript is 1859 bp and has a 45 bp 5' UTR, a Other names: CTLA8, IL-17, IL-17A, IL17 468 bp coding sequence, and a 1346 bp 3' UTR. HGNC (Hugo): IL17A Pseudogene Location: 6p12.2 No pseudogenes homologous to this gene exist Local order: pter - PKHD1 (polycystic kidney and elsewhere in the genome.

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IL17A gene. The IL17A gene spans a region of 4252 bp, consisting of three exons (untranslated region (UTR), light blue; coding region, blue) and two introns (brown). Exons 1, 2, and 3 are 72 bp (45 bp 5' UTR plus 27 bp coding region), 203 bp (all coding regions), and 1584 bp (238 bp coding region plus 1346 bp 3' UTR) in length, respectively. The two introns are 1144 bp and 1249 bp in length.

mature peptide. The IL17A homodimer has a Protein molecular weight of 35 kD (Kolls and Lindén, Note 2004). The IL17A protein is a glycoprotein that can form Expression either a disulfide-linked homodimer or a IL17A is secreted not only by CD4 + T cells (Th17 heterodimer with the IL17F protein. Members of cells), which also produce IL17F, IL21, and IL22 the IL17 protein family (IL17A-F) contain four (Korn et al., 2009; Kurebayashi et al., 2013), but highly conserved cysteine residues on each also by CD8 +T cells (Tc17 cells), γδ T cells, monomer (Kolls and Lindén, 2004; Iwakura et al., invariant natural killer T cells (iNKT cells), innate 2011). Structural analysis of the IL17F protein has lymphoid cells (ILCs) including lymphoid tissue revealed that these four cysteines participate in the inducer cells (LTi cells), B cells, neutrophils, and characteristic cystine-knot formation observed in other non-hematopoietic cells (Cua and Tato, other growth factors such as nerve growth factor 2010). These lymphocytes all express the retinoic (NGF), transforming growth factor β2 (TGF β2) and acid receptor-related orphan nuclear receptor C platelet-derived growth factor (PDGF)-BB (RORC, the human analogue of mouse ROR γt, a (McDonald and Hendrickson, 1993), although one splice variant of the Rorc gene). ROR γt is essential of the canonical disulfides of the cystine-knot is for IL17A production and the development of absent from the IL17 protein family (Hymowitz et IL17A-producing cells, at least in lymphocytes, and al., 2001). Two additional cysteine residues is thus considered a master regulator of IL17A- participate in homodimer formation via inter-chain producing cells. disulfide bonds. Crystal structures are now Th17 cells available for IL17A in complex with an antibody Th17 cells are a subset of helper T cells that have (Gerhardt et al., 2009), an IL17F/IL17 receptor A effector functions distinct from those of Th1 and complex (Ely et al., 2009) and an IL17A/IL17 Th2 cells. Early reports showed that stimulation receptor A complex (Liu et al., 2013). with transforming growth factor β1 (TGF β1) and IL6 is required to induce differentiation of IL17- producing CD4 + T cells (Th17 cells) from naïve CD4 + T cells (Korn et al., 2009). More recent reports have shown that Th17 cells can be categorized into two distinct subsets: conventional Th17 cells (Th17( β) cells, also called non- pathogenic Th17 cells), which differentiate in the presence of IL6 and TGF β1, and Th17(23) cells IL17A protein. The IL17A protein (155 amino acids) (also called pathogenic Th17 cells), which consists of a signal peptide (light green, 23 amino acids) differentiate in the presence of IL6, IL23 and IL1 β and a mature peptide (green, 132 amino acids). Four without exogenous TGF β1 (Ghoreschi et al., 2010; conserved cysteines (Cys) form the intra-chain disulfide bonds indicated by black lines (Cys94/Cys144 and Basu et al., 2013; Kurebayashi et al., 2013). IL6 Cys99/Cys146) (Hymowitz et al., 2001). The two cysteines and IL1 β can induce the expression of IL23 indicated by asterisks (Cys33 and Cys129) participate in receptor in naïve CD4 + T cells in the absence of homodimer formation via inter-chain disulfide bonds. TGF β1. Th17( β) cells express IL9, IL10, CCL20, Asparagine 68 (Asn68, black circle) is predicted to be glycosylated. and CXCR6 as well as IL17A and IL17F, whereas Th17(23) cells express IL22, CCL9 and CXCR3; Description relative to Th17( β) cells, Th17(23) cells make a The IL17A monomer is a peptide consisting of 155 greater contribution to pathogenesis in autoimmune amino acids. The IL17A peptide comprises a 23 diseases (Ghoreschi et al., 2010). Th17 cells amino acid signal peptide and a 132 amino acid stimulated with IL23, which is secreted by dendritic

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 19 IL17A (interleukin 17A) Inoue N, Akazawa T

cells and macrophages following stimulation with CD27 - γδ T cells, a process controlled by ROR γt Toll-like receptor (TLR) ligands, induce expression and RUNX1 (Cua and Tato, 2010; Prinz et al., of TGF β3, leading to the induction of pathogenic 2013). Because peripheral CD27 -γδ T cells have Th17(23) cells (Lee et al., 2012). These pathogenic permissive histone modification at loci involved in Th17 cells are characterized by the expression of T- expression of not only Il17a but also Ifng, they can bet (TBX21, T-box protein 21), a master regulator produce both IL17A and IFN γ upon stimulation of Th1-cell development, as well as ROR γt. with IL1 β and IL23 (Schmolka et al., 2013). All Compared with Th1 and Th2 differentiation, Th17- innate IL17-producing lymphocytes, including γδ T cell differentiation exhibits plastic or flexible cells, iNKT cells and LTi cells, express ROR γt and features (Oestreich and Weinmann, 2012; Basu et develop in an IL6-independent manner (Cua and al., 2013). TGF β1 signaling induces the expression Tato, 2010). of both Foxp3 and ROR γt in antigen-activated iNKT cells naïve CD4 + T cells and is involved in the iNKT cells are activated in response to glycolipid differentiation of both iTreg and Th17 cells. antigens presented by CD1d (Cua and Tato, 2010; Therefore, additional factors determine iTreg and Guo et al., 2012). IL17A-producing iNKT cells Th17 polarization. Furthermore, iTreg and Th17 develop in the thymus, and express ROR γt and cells can transdifferentiate under specific conditions IL23R. A recent report suggested that iNKT cells (Hoechst et al., 2011). The transition from Th17 can be induced to produce IL17A in the presence of cells to Th1 cells is also induced by IL23 and IL12 TGF β1 and IL1 β (Monteiro et al., 2013). in a STAT4- and T-bet-dependent manner (Lee et LTi cells al., 2009; Mukasa et al., 2010). Innate lymphoid cells (ILCs), a family of RAG1/2- In addition to ROR γt and the aforementioned negative lymphoid cells, require the common cytokines, several transcriptional regulators cytokine receptor γ-chain (also known as IL2RG) positively regulate Th17 cell differentiation: signal and inhibitor of DNA binding 2 (ID2), a transducer and activator of transcription 3 (STAT3), transcriptional repressor (Guo et al., 2012; Fuchs BATF (basic leucine zipper transcriptional factor, and Colonna, 2013; Spits et al., 2013). LTi cells, ATF-like), interferon regulatory factor 4 (IRF4), which like NK cells are prototypical ILCs, belong Runt-related transcriptional factor 1 (RUNX1), to the Group 3 ILCs (ILC3s), defined by the ROR α and aryl hydrocarbon receptor (AHR, a production of IL17A and/or IL22 (Spits et al., nuclear receptor for a number of low-molecular 2013). ILC3s require the expression of ROR γt for weight chemicals such as the tryptophan their development, express IL23R and IL1R, and photoproduct 6-formylindolo[3,2-b]carbazole produce IL17A and/or IL22 upon stimulation with (FICZ)) (Hirahara et al., 2010; Kurebayashi et al., IL23 or IL1 β. 2013). Moreover, prostaglandin E2, ATP, and C- B cells type lectin ligands act on antigen-presenting cells to A recent report shows that Trypanosoma crusi facilitate Th17-cell differentiation. By contrast, IL4, promotes IL17A production by B cells in human interferon-γ (IFN γ), IL27, suppressor of cytokine and mouse (Bermejo et al., 2013). T. crusi trans- signaling 3 (SOCS3), and STAT5 all suppress sialidase mediates addition of sialyl residues onto Th17-cell differentiation. CD45 expressed on B cells, resulting in induction Tc17 cells of IL17A and F via BTK activation without the CD8 + T cells develop into Tc17 cells in the involvement of the transcriptional factors ROR γt presence of TGF β1 and either IL6 or IL21, similar and AHR. to the requirements for Th17-cell development Other cells (Intlekofer et al., 2008). Tc17 cells are also Although the details of the underlying signaling characterized by the expression of ROR γt, STAT3, pathways and transcriptional factors are not known, ROR α and IL23R. However, Tc17 cells do not cells other than lymphocytes, such as Paneth cells express Granzyme B, and they exhibit impaired in the gut and CD11b +Gr1 + cells in the injured cytotoxic activity relative to conventional cytotoxic kidney also produce IL17A (Cua and Tato, 2010). CD8 +T cells (Huber et al., 2009). A recent report suggested that TGF β signaling is not required for in Localisation vivo differentiation of Tc17 cells (Dwivedi et al., IL17A is a secreted protein. 2012). Function γδ T cells Two distinct subsets of CD27 + or CD27 - γδ T cells IL17A is a pro-inflammatory cytokine that acts on a develop in the mouse fetal thymus: co-stimulation variety of cells (e.g., fibroblasts, epithelial cells, of TCR and CD27 induces CD27 + γδ T cells to endothelial cells, and monocytes) to induce the express T-bet and produce IFN γ whereas the production of other cytokines, including IL6, tumor absence of TCR signaling (or weak signaling) necrosis factor-α (TNF α), granulocyte-macrophage promotes the development of IL17A-producing colony-stimulating-factor (GMCSF), granulocyte

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colony-stimulating-factor (GCSF), chemokines upregulates expression of ROR γt and IL17A. (chemokine (C-X-C motif) ligand 1 (CXCL1), Therefore, amino acid deprivation selectively CXCL2, CXCL5, and CXCL8), antimicrobial blocks Th17-cell development through inhibition of peptides (defensins) and matrix metalloproteinases mTORC1, whereas hypoxia promotes Th17 (MMP1, MMP3, and MMP13) (Eyerich et al., development through the activation of HIF1 α. High 2010; Iwakura et al., 2011). These factors mediate levels of lactic acid, secreted from tumors due to the recruitment, activation and migration of the Warburg effect, induce macrophages or neutrophils and myeloid cells, and also induce monocytes to mediate increased IL17A production angiogenesis and tissue destruction. by Th17 cells in an antigen-dependent manner, but IL17A, IL17F, and the IL17A-IL17F heterodimer do not Th17-cell differentiation or proliferation bind to a heteromeric receptor complex composed (Shime et al., 2008; Yabu et al., 2011). of IL17 receptor A (IL17RA) and IL17 receptor C The circadian rhythm is controlled by a series of (IL17RC). IL17RA is expressed at high levels in feedback loops between the transcriptional factors, hematopoietic cells and at low levels in epithelial a CLOCK-BMAL1 complex and REV-ERB α cells, fibroblasts, and endothelial cells (Gaffen, (Arjona et al., 2012). The expression of ROR γt is 2009; Iwakura et al., 2011). On the other hand, suppressed by the leucine zipper transcriptional IL17RC is expressed at low levels in hematopoietic factor NFIL3, which is negatively regulated by cells and at high levels in the adrenal gland, REV-ERB α (Yu et al., 2013). Accordingly, CD4 + T prostate, liver, and thyroid. IL17RA has higher cells purified during the day express ROR γt at affinity for IL17A than IL17F, whereas IL17RC has higher levels than those purified at night, and tend higher affinity for IL17F than IL17A. Although to differentiate into Th17 cells. cytokines secreted by most activated helper T cells High salt concentration (e.g., 40 mM NaCl) induces generally stimulate the Janus kinase (JAK)/STAT phosphorylation of p38 and the expression of serum pathway, the IL17-family cytokines stimulate glucocorticoid kinase 1 (SGK1) and nuclear factor signaling pathways involved in the innate immune of activated T-cells 5 (NFAT5) to promote the system, such as the TLR signaling pathway IL23-dependent differentiation of pathogenic Th17 (Gaffen, 2009; Iwakura et al., 2011). cells (Kleinewietfeld et al., 2013; Wu et al., 2013a). IL17 receptors contain a conserved domain, 'similar In vivo, a high salt diet promotes Th17-cell expression to fibroblast growth factor/IL17R' differentiation and exacerbates neuropathy in mice (SEFIR), in the cytoplasmic region. This domain is with experimental autoimmune encephalomyelitis. similar to the Toll-/IL1R (TIR) domain (Gaffen, Homology 2009; Iwakura et al., 2011). When the IL17 receptor is activated, the adaptor molecule actin-related gene IL17A is a prototypical member of the IL17 family. 1 (ACT1, a U-box E3 ubiquitin ligase) is recruited This family includes six proteins: IL17A, IL17B, to the SEFIR domain and mediates the lysine 63- IL17C, IL17D, IL17E (also called IL25), and linked ubiquitination of tumor necrosis factor IL17F. Interleukins 17A-F are not homologous to receptor-associated factor 6 (TRAF6) (Gaffen, any other known proteins. IL17A has the highest 2009; Iwakura et al., 2011). Ubiquitinated TRAF6 sequence identity with IL17F (46.5 %). It is less then activates the transcriptional factor nuclear similar to the other IL17 family members: IL17B, factor κB (NF κB), various mitogen-activated 26.4 %; IL17C, 28.9 %; IL17D, 21.8 %; and IL17E, protein (MAP) kinases including ERKs and p38, 17.7 %. and CCAAT/enhancer-binding proteins (C/EBP β and C/EBP δ). Implicated in IL-17A expression and Th17 cell development are remarkably affected not only by microorganisms Ovarian cancer and tumors, but also by several environmental Note factors such as nutrients, metabolites, hypoxia, Tumor infiltration by Th17 cells is positively toxins, NaCl concentrations, and circadian rhythm. correlated with infiltration by Th1 cells, IFN γ- The tryptophan photoproduct FICZ positively producing CD8 + cells (Tc1 cells), IL17A- and regulates Th17-cell differentiation through AHR, IFN γ-double-positive T cells, and NK cells, but whereas 2,3,7,8-tetrachlorodibezo-p-dioxin negatively correlated with the presence of Treg (TCDD) negatively regulates differentiation cells (Kryczek et al., 2009a). Increased IL17A through that receptor (Quintana et al., 2008; levels in ascites are well correlated with better Veldhoen et al., 2008). Activation of mTORC1 patient survival and lower grades of ovarian cancer. (mTOR complex containing mLST8 and Raptor) Esophageal cancer promotes Th17-cell differentiation via positive regulation of hypoxia-inducible factor 1 α (HIF1 α Note expression and the activation of S6 kinase (Barbi et Elevated levels of IL17A-producing cells, including al., 2013; Kurebayashi et al., 2013). HIF1 α directly Th17 cells, in esophageal cancer tissues are

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associated with the intratumoral accumulation of (Qinghai et al., 2014; Zhang et al., 2014a). The TT- CD8 + T and NK cells, as well as with better genotype of the SNP rs3748067, which is localized prognosis (Lv et al., 2011). in 3' UTR of the IL17A gene (C/T SNP, a position Prostate cancer at 52055339 bp from pter), was associated with increased risk of gastric cancer in two studies Note (Qinghai et al., 2014; Zhang et al., 2014a). In prostate tumors, elevated levels of Th17 cells are associated with a lower pathologic Gleason scores Colorectal cancer (Sfanos et al., 2008). However, in prostate cancer Note patients, a higher frequency of CCR4 - Th17 cells in Elevated levels of IL17A-producing cells are peripheral blood is correlated with shorter time to associated with poor prognosis as a result of metastatic progression after immunotherapy with an increased VEGFA expression in colorectal cancer allogeneic whole-cell vaccine (Derhovanessian et patients (Liu et al., 2011; Tosolini et al., 2011; Wu al., 2009). et al., 2013b). Furthermore, the A-allele of SNP Gastric cancer rs2275913 is positively associated with susceptibility to colorectal cancer, as well as with Note clinical features as tumor location, tumor The relationship between IL17A and gastric cancer differentiation, and TNM stage (Omrane et al., is controversial. Expression of IL17A in peripheral 2014). In a mouse model of colorectal cancer, loss blood mononuclear cells (PBMC) and gastric of effective barrier function in the transformed cancer tissue is elevated, especially in patients with epithelial cells of colonic adenoma results in the advanced-stage gastric cancer (Zhang et al., 2008; infiltration of non-pathogenic bacteria and their Zhuang et al., 2012; Su et al., 2014). One group products, leading to the production of inflammatory suggested that increased infiltration of Tc17 cells in cytokines (including IL23 and IL17A) and the tissues is associated with higher stages and lower induction of tumor-elicited inflammation, which overall survival rates (Zhuang et al., 2012). Th17 promotes tumor development (Grivennikov et al., cells also infiltrate tumors, but the percentage of 2012). Th17 cells is lower than that of Tc17 cells. CXCL12, which is produced by tumors stimulated Hepatocellular cancer with IL17A, promotes the recruitment of CXCR4- Note dependent MDSCs and suppresses the function of In patients with hepatocellular carcinoma, increased + the cytotoxic CD8 T cells (Zhuang et al., 2012). intratumoral accumulation of IL17A-producing However, another group's report showed that cells is significantly associated with poor prognosis intratumoral expression of IL17A is associated with and increased tumor vasculogenesis (Zhang et al., good prognosis (Chen et al., 2011). Several studies 2009). have examined the relationship between gastric cancer risk and a single nucleotide polymorphism Uterine cervical cancer (SNP) in the IL17A gene promoter region. This Note SNP (rs2275913, G/A SNP, 52051033 bp from Levels of Tc17 cells are higher in PBMCs and pter) is located at position -197 relative to the start tumors of uterine cervical cancer patients with codon within the NFAT-binding motif. The A- lymph-node metastasis than in patients without allele is associated with higher IL17A promoter metastasis (Zhang et al., 2014b). Higher activity and higher affinity for NFAT, which plays accumulation of Tc17 cells in tumors is associated critical roles in the IL17A production, than the G- with a greater degree of tumor vasculogenesis and allele (Espinoza et al., 2011). Studies of the increased infiltration by Th17 cells and Treg cells. association between rs2275913 and gastric cancer In Chinese women, the AA-genotype and A-allele have yielded different results in different of IL17A polymorphism rs2275913 are positively populations. Four groups reported that the AA- associated with susceptibility, peritumoral genotype and A-allele of SNP rs2275913 are intravascular cancer emboli, and high clinical stage significantly associated with gastric cancer risk in (Quan et al., 2012). Japanese (Shibata et al., 2009), Iranian (Rafiei et al., 2013), and Chinese populations (Qinghai et al., Breast cancer 2014; Zhang et al., 2014a), whereas one Chinese Note group reported that this SNP is not associated with Increased infiltration of IL17A-producing cells in total cancer risk or survival in gastric cancer tissues is associated with shorter disease-free patients (Wu et al., 2010). Two studies suggested survival in breast cancer patients and higher that this SNP is significantly associated with gastric histopathological grades (Chen et al., 2013). cancer risk in Helicobacter pylori-infected patients, Among Han Chinese women, the frequency of the smokers, or non-cardia gastric cancer patients AA-genotype of the IL17A SNP rs2275913 is also

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higher in patients than controls (Wang et al., 2012). bacterium Staphylococcus aureus in the skin, and IL17A-producing T cells and Treg cells are the fungus Candida albicans in the mouth; IL17A synchronically increased in peripheral blood and appears to protect against all of these types of tumor tissues of breast cancer patients relative to infections (Korn et al., 2009; O'Connor et al., 2010; those of healthy individuals (Benevides et al., Iwakura et al., 2011). During the early response to 2013). Levels of the angiogenic factors CXCL8, infection, IL17A is predominantly secreted by γδ T MMP-2, MMP-9, and VEGFA, which are induced cells and iNKT cells, and it induces the production by IL17A, are also elevated in breast cancer tissue. of antimicrobial peptides such as β-defensins, Thus, IL17A is an important prognostic factor in regenerating (REG) proteins, and S100 proteins, as breast cancer. well as granulopoietic factors such as GCSF and Lung cancer CCL20, from epithelial cells (Cua and Tato, 2010). This results in the rapid recruitment of neutrophils Note to sites of infection, which in turn promotes Higher levels of IL17A-producing cells are efficient pathogen clearance. Later, antigen-specific associated with poor prognosis and increased αβ Th17 cells contribute to further responses to lymphangiogenesis in non-small cell lung cancer infection. tissues (Chen et al., 2010). Although no significant Cancers in mouse models relationship between SNP rs2275913 in the IL17A gene and lung cancer risk has been observed in the Note total Tunisian population, the A-allele is associated Elevated expression of IL17A and increased with increased lung cancer risk in the male and accumulation of IL17A-producing cells in the smoker subgroups (Kaabachi et al., 2014). tumor microenvironment are associated with anti- tumor or pro-tumor effects in various types of Bladder cancer cancer in human patients and mouse models (Zou Note and Restifo, 2010). Although IL17A-producing The frequency of the AA-genotype and A-allele of cells are not the dominant T-cell subset in the tumor SNP rs2275913 in bladder cancer patients is microenvironment, their levels are elevated to a significantly higher than in control Han Chinese greater extent in the tumor site than in peripheral populations (Zhou et al., 2013). This SNP is also blood of patients (Kryczek et al., 2009a). Recent associated with increased bladder cancer risk in reports have suggested that the increased males and non-smokers, as well as with invasion of accumulation of not only Th17 cells, but also Tc17 bladder cancer. (Hinrichs et al., 2009; Zhuang et al., 2012), IL17- producing γδ T cells (Wakita et al., 2010; Schmolka Autoimmune and inflammatory et al., 2013), and ILC3s (Kirchberger et al., 2013), diseases regulates tumor development. Note Overexpression of IL17A in tumor cells suppresses IL17-producing cells are associated with the tumor growth in a cytotoxic T lymphocyte- pathogenesis of many autoimmune and dependent manner (Benchetrit et al., 2002). The inflammatory diseases, such as EAE/multiple transfer of tumor antigen-specific T cells polarized sclerosis, inflammatory skin diseases/psoriasis, to the IL17-producing phenotype also induces + inflammatory bowel diseases, ankylosing eradication of tumor cells by inducing strong CD8 spondylitis, and experimental arthritis/rheumatoid T-cell activation (Martin-Orozco et al., 2009). arthritis, in both human patients and mouse models Furthermore, deficiency of IL17A in mice promotes (Awasthi and Kuchroo, 2009; Korn et al., 2009). growth and metastasis of tumors (Kryczek et al., Recent reports have shown that treatment of 2009b; Martin-Orozco et al., 2009). IL17A- psoriasis patients with the antibodies that neutralize producing T cells are predicted to induce IL17A and IL17A-IL17F heterodimer or block recruitment of other effector cells (e.g., cytotoxic + IL17RA results in reduction in the affected skin CD8 T cells and NK cells) to tumors by inducing area and disease severity (Leonardi et al., 2012; expression of CXCL9 and CXCL10 within tumor Papp et al., 2012). Thus, therapies targeting the sites (Kryczek et al., 2009a). Moreover, Th17 cells IL17A signaling pathway are predicted to be induce expression of CCL20, a ligand for effective in psoriasis patients. chemokine (C-C motif) receptor 6 (CCR6), in tumor tissues. CCL20 recruits dendritic cells, which Infections mediate anti-tumor effects in a CCL20/CCR6- Note dependent manner (Martin-Orozco et al., 2009). Both IL17A and IL17F are preferentially produced On the other hand, overexpression of IL17A in during infections with the Gram-negative bacteria tumors facilitates tumor growth by inducing Klebsiella pneumoniae in the lungs and Citrobacter angiogenesis in the tumor microenvironment rodentium in the colon, the Gram-positive (Numasaki et al., 2003; Numasaki et al., 2005).

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Furthermore, IL17A-deficient or IL17RA-deficient Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, mouse models were used to show that IL17A was Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl involved in the promotion of tumor growth via hydrocarbon receptor. Nature. 2008 May 1;453(7191):65- induction of myeloid-derived suppressor cells 71 (MDSC) (He et al., 2010), activation of IL6-STAT3 Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, pathway (Wang et al., 2009), and elevated DeMarzo AM, Meeker AK, Isaacs WB, Drake CG. angiogenesis (Wakita et al., 2010). The Phenotypic analysis of prostate-infiltrating lymphocytes discrepancies between anti-tumor and pro-tumor reveals TH17 and Treg skewing. Clin Cancer Res. 2008 effects may be due to the distinct roles of IL17A- Jun 1;14(11):3254-61 producing cells in different tumors. 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J Exp Med. 2013 May polymorphisms on the risk of gastric cancer in a Chinese 6;210(5):917-31 population. Gene. 2014 Mar 10;537(2):328-32 Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Su Z, Sun Y, Zhu H, Liu Y, Lin X, Shen H, Chen J, Xu W, Linker RA, Muller DN, Hafler DA. Sodium chloride drives Xu H. Th17 cell expansion in gastric cancer may contribute

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to cancer development and metastasis. Immunol Res. Zhang Y, Hou F, Liu X, Ma D, Zhang Y, Kong B, Cui B. 2014 Jan;58(1):118-24 Tc17 cells in patients with uterine cervical cancer. PLoS One. 2014b;9(2):e86812 Zhang X, Zheng L, Sun Y, Zhang X. Analysis of the association of interleukin-17 gene polymorphisms with This article should be referenced as such: gastric cancer risk and interaction with Helicobacter pylori infection in a Chinese population. Tumour Biol. 2014a Inoue N, Akazawa T. IL17A (interleukin 17A). Atlas Genet Feb;35(2):1575-80 Cytogenet Oncol Haematol. 2015; 19(1):18-27.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 27

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MAGEA3 (melanoma antigen family A, 3) Biswajit Das, Sujit Suklabaidya, Sumeet Jain, Manas R Baisakh, Shantibhusan Senapati Institute of Life Sciences, Bhubaneswar, Odisha 751023, India (BD, SS, SJ, SS), Apollo Hospital, Bhubaneswar, Odisha 751003, India (MRB)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAGEA3ID41247chXq28.html DOI: 10.4267/2042/55374 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAGEA3 has drawn paramount attention as an Abstract anti-cancer immunotherapy. In the year 1991 Van der Bruggen P et al. cloned and named MAGE-1 gene that encodes MZ2E DNA/RNA antigen, which is expressed in melanoma tissues and cell lines (van der Bruggen et al., 1991). Description Since then based on sequence similarity MAGE In human X chromosome; MAGEA3, is clustered family has expanded to more than 60 genes in q28 along with other MAGEA sub-family (Chomez et al., 2001). members. The gene consists of three exons and is According to their chromosomal location and distributed over 3588 bp (Figure 1). tissue-specific expression pattern, all the members Transcription of this family are categorized into two groups; type I (cancer and testis specific) and type II MAGEA3 gets transcribed from the reverse (ubiquitous) MAGE. (minus/negative) strand of the DNA. The transcript MAGEA sub-family has 12 members starting from or m-RNA harbors three exons, but only the 3rd MAGEA1 to MAGEA12, among them MAGEA7 exon contributes to the whole ORF (Figure 1). is a pseudo-gene (Doyle et al., 2010). Three transcript variants have been reported till The current review summarizes the information date. specifically on MAGEA3's DNA/RNA, protein structure, function and where the gene is Protein implicated. Description Identity The MAGEA3 protein consists of 314 amino acids. The protein has a molecular weight of 34747 Da Other names: CT1.3, HIP8, HYPD, MAGE3, and pI 4.57. Like other MAGEA family members, MAGEA6 it has a conserved MAGE homology domain HGNC (Hugo): MAGEA3 (MHD; 116 aa - 286 aa) (Sang et al., 2011). Unfortunately, till date no clear functional role has Location: Xq28 been identified for this domain. The protein has Note also one MAGE NH 2-terminal and one MAGE MAGEA3 is the third member of MAGEA CT- COOH-terminal region in its structure (Figure 1). antigen family. Due to its restricted expression in The MAGEA3 protein is 85% and 95% identical to normal testicular and placental trophoblast cells and MAGEA2 and MAGEA6, respectively aberrant expression in various types of cancer cells, (Atanackovic et al., 2010).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 28 MAGEA3 (melanoma antigen family A, 3) Das B, et al.

Figure 1. Genomic organization and protein domain structure of MAGEA3.

Expression p53 target genes in response to DNA damage (Monte et al., 2006). The expression of MAGEA3 is restricted to germ Moreover, MAGEA3 directly interacts with and cells of testis (primary spermatocytes and enhances the ubiquitin ligase activity of TRIM28 (a spermatogonia) and placental trophoblast, but no RING E3 ubiquitin ligase) and has a probable role other somatic cellular expression have been in p53 degradation (Doyle et al., 2010). Its other reported except in wide variety of tumor cells. functional implications in various cancer cells are Localisation mentioned in this report. MAGEA family members Cytoplasmic and nuclear expression has been have significant protein sequence identity, which reported (Atanackovic et al., 2010; Barker and suggests a functional similarity among them. Salehi, 2002; Guo et al., 2013). However, a distinct variability in the regulatory regions of MAGEA genes suggests a possible Function molecular mechanism of carrying out the same Since the MAGA3 protein is restricted to germ cell function by different members, under different of testis and trophoblast of placenta which are transcription control. immune privileged tissues, the protein is highly Regulation immunogenic and recognized by CTLs when Till now demethylation of promoter region has expressed elsewhere. been reported as the major regulatory mechanism Its role in spermatogenesis and embryo that leads to unusual derepression of MAGEA3 in development is still unknown. cancer cells (Figure 2). Histone acetylation is also A report says MAGEA3 has the ability to repress reported to regulate the expression of MAGEA3 in p53 function/transactivation, and MAGEA3 cancer cells (Kim et al., 2006b; Wischnewski et al., knockdown results in increased accumulation of 2006).

Figure 2. Role of MAGEA3-promoter methylation in spatiotemporal regulation of MAGEA3 gene expression.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 29 MAGEA3 (melanoma antigen family A, 3) Das B, et al.

The MAGEA3 promoter is found to be Thyroid carcinoma hypermethylated in response to FGFR2-IIIb and/or Note FGF7 stimulating signals resulting into MAGEA3 MAGEA3 expression has been detected in patient silencing in MAGEA3-positive thyroid cancer cell tissue samples and its expression was high in the lines (Kondo et al., 2007). small papillary carcinoma. MBD1, a methyl-CpG Binding Domain protein is Experimental evidences suggest a possible reported to have the ability to bind the functional role of MAGEA3 in thyroid carcinoma unmethylated promoter of MAGEA3 and cells' growth, invasion and metastasis (Liu et al., suppresses the promoter activity that cannot be 2008). retracted by Ets-1 transcription factor (Wischnewski et al., 2007). Breast cancer Homology Note Around eight different organisms have orthologs MAGEA3 mRNA expression has been reported in with human MAGEA3. breast cancer patient tissue samples. Detection of MAGEA3 mRNA in the sentinel Implicated in lymph nodes (SLN) of breast cancer patients indicates a high chance of micro-metastasis. Various cancers It is mostly expressed in the intermediate or poorly differentiated primary breast carcinoma, which is Note associated with poor prognosis and contributes to MAGEA3 expression is being reported in colorectal higher recurrence rate (Otte et al., 2001; Wascher et cancer, breast cancer (10%), bladder cancer (37%), al., 2001). pancreatic cancer (40%), multiple myeloma (41%), gastric cancer (48%), glioma (51.3%), melanoma Lung cancer (NSCLC) (65%), thyroid cancer (65%) and NSCLC (85%). Note Information about MAGEA3 expression and MAGEA3 mRNA expression has been reported in significance in various malignancies is mentioned lung cancer patient tissue samples. below. High level of MAGEA3 is a potential marker for Pancreatic ductal adenocarcinoma poor prognosis in NSCLC patients (Gure et al., 2005). Note MAGEA3 expression has been reported in Non-Hodgkins lymphoma pancreatic cancer cell lines and tissues. Note Its expression significantly correlates with poor MAGEA3 expression has been detected both in cell prognosis in pancreatic cancer patients (Cogdill et lines and tissue samples (at RNA level). MAGEA3 al., 2012; Kim et al., 2006a; Kubuschok et al., in peripheral blood of patients can be a potential 2004). tumor marker and is a therapeutic target (Han et al., Colorectal cancer 2010). Note Leukemia Colorectal cancer cell lines express MAGEA3 and Note its expression in tumor tissue samples significantly High level of MAGEA3 expression significantly correlates with tumor size (Kim et al., 2006b; correlates with higher bone marrow blast (Martínez Shantha Kumara et al., 2012). et al., 2007). Multiple myeloma Glioma Note Note MAGEA3 expression has been detected in multiple MAGE3 protein has been detected in glioma tissue myeloma cell lines and patients samples. samples. Its expression level does not reflect Its expression correlates with disease progression significant difference in overall survival of patients i.e. the frequency of expression is higher in relapsed between the pathological grades (Guo et al., 2013). patients than newly diagnosed individuals. Further, silencing of MAGEA3 induced intrinsic Gastric cancer apoptosis pathway in proliferating multiple Note myeloma cells, which indicates the functional role Gastric cancer cell lines express MAGEA3; of MAGEA3 in inhibiting apoptosis of cancer cells however, no functional data has been reported till (Atanackovic et al., 2010; Nardiello et al., 2011). date (Honda et al., 2004).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 30 MAGEA3 (melanoma antigen family A, 3) Das B, et al.

target of fibroblast growth factor receptor 2-IIIb through References histone H3 modifications in thyroid cancer. Clin Cancer Res. 2007 Aug 15;13(16):4713-20 van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T. A gene Martínez A, Olarte I, Mergold MA, Gutiérrez M, Rozen E, encoding an antigen recognized by cytolytic T lymphocytes Collazo J, Amancio-Chassin O, Ordóñez RM, Montesinos on a human melanoma. Science. 1991 Dec JJ, Mayani H, McCurdy DK, Ostrosky-Wegman P, Garrido- 13;254(5038):1643-7 Guerrero E, Miranda EI. mRNA expression of MAGE-A3 gene in leukemia cells. Leuk Res. 2007 Jan;31(1):33-7 Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S. An overview of the MAGE gene family with the Wischnewski F, Friese O, Pantel K, Schwarzenbach H. identification of all human members of the family. Cancer Methyl-CpG binding domain proteins and their involvement Res. 2001 Jul 15;61(14):5544-51 in the regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 gene promoters. Mol Cancer Res. 2007 Otte M, Zafrakas M, Riethdorf L, Pichlmeier U, Löning T, Jul;5(7):749-59 Jänicke F, Pantel K. MAGE-A gene expression pattern in primary breast cancer. Cancer Res. 2001 Sep Liu W, Cheng S, Asa SL, Ezzat S. The melanoma- 15;61(18):6682-7 associated antigen A3 mediates fibronectin-controlled cancer progression and metastasis. Cancer Res. 2008 Oct Wascher RA, Bostick PJ, Huynh KT, Turner R, Qi K, 1;68(19):8104-12 Giuliano AE, Hoon DS. Detection of MAGE-A3 in breast cancer patients' sentinel lymph nodes. Br J Cancer. 2001 Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens Nov 2;85(9):1340-6 T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, Kröger N. Cancer- Barker PA, Salehi A. The MAGE proteins: emerging roles testis antigens MAGE-C1/CT7 and MAGE-A3 promote the in cell cycle progression, apoptosis, and neurogenetic survival of multiple myeloma cells. Haematologica. 2010 disease. J Neurosci Res. 2002 Mar 15;67(6):705-12 May;95(5):785-93 Honda T, Tamura G, Waki T, Kawata S, Terashima M, Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE- Nishizuka S, Motoyama T. Demethylation of MAGE RING protein complexes comprise a family of E3 ubiquitin promoters during gastric cancer progression. Br J Cancer. ligases. Mol Cell. 2010 Sep 24;39(6):963-74 2004 Feb 23;90(4):838-43 Han MH, Eom HS, Park WS, Yun T, Park S, Kim HJ, Jeon Kubuschok B, Xie X, Jesnowski R, Preuss KD, Romeike CH, Kong SY. Detection of circulating lymphoma cells in BF, Neumann F, Regitz E, Pistorius G, Schilling M, patients with non-Hodgkin lymphoma using MAGE-A3 Scheunemann P, Izbicki JR, Löhr JM, Pfreundschuh M. gene expression in peripheral blood. Leuk Res. 2010 Expression of cancer testis antigens in pancreatic Sep;34(9):1127-31 carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis. Int J Cancer. 2004 Apr 20;109(4):568- Nardiello T, Jungbluth AA, Mei A, Diliberto M, Huang X, 75 Dabrowski A, Andrade VC, Wasserstrum R, Ely S, Niesvizky R, Pearse R, Coleman M, Jayabalan DS, Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA, Bhardwaj N, Old LJ, Chen-Kiang S, Cho HJ. MAGE-A Gnjatic S, Ritter G, Simpson AJ, Chen YT, Old LJ, Altorki inhibits apoptosis in proliferating myeloma cells through NK. Cancer-testis genes are coordinately expressed and repression of Bax and maintenance of survivin. Clin are markers of poor outcome in non-small cell lung cancer. Cancer Res. 2011 Jul 1;17(13):4309-19 Clin Cancer Res. 2005 Nov 15;11(22):8055-62 Sang M, Lian Y, Zhou X, Shan B. MAGE-A family: Kim KH, Choi JS, Kim IJ, Ku JL, Park JG. Promoter attractive targets for cancer immunotherapy. Vaccine. hypomethylation and reactivation of MAGE-A1 and MAGE- 2011 Nov 3;29(47):8496-500 A3 genes in colorectal cancer cell lines and cancer tissues. World J Gastroenterol. 2006a Sep 21;12(35):5651-7 Cogdill AP, Frederick DT, Cooper ZA, Garber HR, Ferrone CR, Fiedler A, Rosenberg L, Thayer SP, Warshaw AL, Kim J, Reber HA, Hines OJ, Kazanjian KK, Tran A, Ye X, Wargo JA. Targeting the MAGE A3 antigen in pancreatic Amersi FF, Martinez SR, Dry SM, Bilchik AJ, Hoon DS. cancer. Surgery. 2012 Sep;152(3 Suppl 1):S13-8 The clinical significance of MAGEA3 expression in pancreatic cancer. Int J Cancer. 2006b May Shantha Kumara HM, Grieco MJ, Caballero OL, Su T, 1;118(9):2269-75 Ahmed A, Ritter E, Gnjatic S, Cekic V, Old LJ, Simpson AJ, Cordon-Cardo C, Whelan RL. MAGE-A3 is highly Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, expressed in a subset of colorectal cancer patients. Pierotti MA, Rodolfo M, Schneider C. MAGE-A tumor Cancer Immun. 2012;12:16 antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to Guo L, Sang M, Liu Q, Fan X, Zhang X, Shan B. The chemotherapeutic agents. Proc Natl Acad Sci U S A. 2006 expression and clinical significance of melanoma- Jul 25;103(30):11160-5 associated antigen-A1, -A3 and -A11 in glioma. Oncol Lett. 2013 Jul;6(1):55-62 Wischnewski F, Pantel K, Schwarzenbach H. Promoter demethylation and histone acetylation mediate gene This article should be referenced as such: expression of MAGE-A1, -A2, -A3, and -A12 in human cancer cells. Mol Cancer Res. 2006 May;4(5):339-49 Das B, Suklabaidya S, Jain S, Baisakh MR, Senapati S. MAGEA3 (melanoma antigen family A, 3). Atlas Genet Kondo T, Zhu X, Asa SL, Ezzat S. The cancer/testis Cytogenet Oncol Haematol. 2015; 19(1):28-31. antigen melanoma-associated antigen-A3/A6 is a novel

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 31

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RRM2 (ribonucleotide reductase M2) Ali Afrasiabi, Hamid Fiuji, Reza Mirhafez, Amir Avan Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran and Department of ENT-Head and Neck Surgery, ENT-Head and Neck Surgery Research Center, Rasool Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (AAf), Department of Biochemistry, Faculty of Science, Payame Noor University, Mashhad, Iran (HF), Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (RM), Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (HF, AAv)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/RRM2ID42175ch2p25.html DOI: 10.4267/2042/55375 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Identity Ribonucleotide reductase subunit M2 (RRM2) is Other names: R2, RR2, RR2M located in chromosome-2 p25-p24, converts HGNC (Hugo): RRM2 ribonucleotides to deoxynucleotides which is required for DNA polymerization and repair. It has Location: 2p25.1 been shown that RMM2 plays a key role in DNA Local order synthesis, cell growth, and drug resistance of cancer Based on MapViewer, gene flanking RRM2 cells. There is accumulating evidence that alteration oriented on 2p25-p24 are: in the expression level of RRM2 can have a - KLF11 (Kruppel-like factor 11); 2p25, substantial impact on the biological characteristics - CYS1 (cystin 1); 2p25.1, of cancer cells, including tumor initiation and - RRM2 (ribonucleotide reductase M2); 2p25-p24, progression, suggesting its role as a prognostic - C2orf48 (chromosome 2 open reading frame 48); factor and a possible therapeutic target for cancer 2p25.1, therapy. Therefore, this review highlights several - MIR4261 (microRNA 4261); chromosome 2, recent and clinically relevant aspects of the - HPCAL1 (hippocalcin-like 1); 2p25.1. expression and function of RRM2 in human cancer.

Table 1. Exons and introns of RRM2 gene.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 32 RRM2 (ribonucleotide reductase M2) Afrasiabi A, et al.

Figure 1. Ribonucleotide reductase subunit M2 (RRM2) is located in chr 2p25-p24. Synthesis of the encoded protein RRM2 is regulated in a cell-cycle dependent fashion and elevated to maximal levels during S-phase of cell cycle. RRM2 has two isoforms with different N-terminal lengths, variant 1 and 2, which contains 3452 and 3284 bp, respectively.

kbp mRNA RRM2 initiates at position -187 (Zhou DNA/RNA and Yen, 2001). Description Synthesis of the encoded protein (RRM2) is RRM2 gene has ten exons, nine introns and regulated in a cell-cycle dependent fashion and alternative promoters (Table 1). The alternative elevated to maximal levels during S-phase of cell promoters are resulting in two isoforms with cycle (Figure 1). RRM2 promoter has transcription different N-terminal lengths (variants 1 and 2; factor binding sites for SP1, c-Ets, MZF1, E2F, Figure 1). Variants 1 and 2 contain 3452 and 3284 Lyf-1, GATA-X, HSF2, AP-1, CdxA, IK-2, Sox-5, bp, respectively. Variant 1 is the longest isoform SRY, Brn-2, HNF-1, STATx, GATA-1, USF (c- with respect to the variant 2. Myc), Pbx-1, Oct-1, GATA-2, CRE-Bp and Nkx-2. 3.4 kbp RRM2 mRNA is the major form in kidney, Transcription placenta and lung, while 1.65 kbp RRM2 mRNA is Promoter of RRM2 gene has two transcription start the main form in small intestine, colon, testis and sites, TATA box, three CCAAT boxes and several thymus. RRM2 gene expression level is high in GC rich in 5' of the downstream transcription small intestine, colon thymus and testis tissues. In initiation site. Variant 2 has a shorter 5' UTR and addition RRM2 mRNA in heart is very higher with uses a downstream translational start codon, respect to other tissues. Conversely, the expression compared to the variant 1. Regions of -204 to +1 level of RRM2 gene is low in lung and liver tissues, and -659 to -257 act as a promoter for the variant 1 and its level is very low level in prostate, skeletal (1.65 kbp) and variant 2 (3.4 kbp), respectively. muscle, brain and leukocyte tissues (Zhou and Yen, Several studies are currently ongoing for the role of 2001; Park and Levine, 2000). the 3' UTR in the regulation of RRM2 expression. Moreover, three CCAAT boxes exist in the region Pseudogene between transcription initiating sites at positions - Related pseudogenes have been identified on 82, -109, -139 and -436. Also, the transcription of chromosomes 1 and X (1p33 →p31, 1q21 →q23 and 1.65 kbp RRM2 mRNA initiates from +1, while 3.4 Xp21 →p11).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 33 RRM2 (ribonucleotide reductase M2) Afrasiabi A, et al.

Table 2. Percentage of identity/homology of RRM2 in DNA and protein levels in eukaryotes with respect to human.

producing a stable tyrosyl radical for the active site Protein of RNR that is located in RRM1. In addition, Description p53R2 is 80% similar to RRM2, which can bind to The building blocks of DNA, deoxyribonucleotide RRM1 and form the active structure. According to triphosphates (dNTPs), is provided/generated by the vital role of RNR in cell cycle and proliferation, ribonucleotide reductases (RNR). In fact RNR have RNRs can be considered as suitable targets for a vital role in preserving the appropriate amount of cancer treatment. dNTPs (dATP, dGTP, dCTP, dTTP) pool for DNA Several studies have been demonstrated that replication and repair by converting ribonucleotide inhibition of RRM2 can inhibit cancer cell growth diphosphates (NDP) to deoxyribonucleotide and overcomes drug resistance (Aimiuwu et al., diphosphates (dNDP). RNR enzymes are divided 2012; Zhou et al., 2013). into three different classes: I, II and III. Human In particular, Zhou and colleagues showed that RNR belongs to the class I. Furthermore, RNR has inhibition of RRM2 by novel RNR inhibitor two subunits, RRM1 and RRM2. RRM1 is the COH29 inhibited the proliferation of most cell lines larger subunit of RNR with respect to the RRM2. in the human cancer panel, mostly ovarian cancer RRM2 isoform 1 and 2 have 449 and 389 residues, and leukemia. In mouse xenograft models of human respectively. In particular, isoform 1 has 60 cancer, COH29 treatment reduced tumor growth residues more than isoform 2 inits N-terminal with respect to the control group (Zhou et al., region. RRM2 interact with RRM1 through its C- 2013). terminus region (Nordlund and Reichard, 2006; Homology Eklund et al., 2001; Thelander, 2007). The RRM2 gene is conserved in Rhesus monkey, Expression dog, chicken, cow, mouse, rat, K. lactis, fruit fly, RRM2 protein expression is increased to maximal mosquito, C. elegans, M. oryzae, S. cerevisiae, S. level during S-phase due to E2F, as an activator of pombe, E. gossypii, N. crassa, and A. thaliana. DNA synthesizing enzymes, however, its exression Percentage of identity or homology of RRM2 in is reduced during G1 by E2F4 (Eklund et al., 2001; DNA and protein levels in eukaryots with respect to Nordlund and Reichard, 2006). human is shown in Table 2. Function Mutations RRM2 contains a KEN-box on the N-terminus that is recognized during the mitosis by the Cdh1- Note anaphase-promoting complex and thereby becomes More than 1215 single nucleotide variations (SNPs) poly-ubiquitinated or depredates by proteasome have been reported in RRM2 gene (until 5th of (Nordlund and Reichard, 2006; Eklund et al., 2001; March 2014, dbSNP), such as rs15516, rs1130609, Thelander, 2007). RRM2 is responsible for rs1138727, rs1138728, rs1138729, rs4668664, etc.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 34 RRM2 (ribonucleotide reductase M2) Afrasiabi A, et al.

mRNA levels were determined by quantitative PCR Implicated in and correlated with response, time to progression Pancreatic cancer and survival. This study showed that the probability of response decreased (RRM2: Odds Ratio, 0.94; Note p<0.0001) and the risk of progression increased Youns and colleagues recently showed that RRM2 (RRM2: HR, 1.005; p = 0.01) in patients samples is overexpressed in the pancreatic cancer cell lines. with high expression of RRM2, compared to the They performed a gene expression profiling to samples with low expression (Boukovinas et al., identify novel molecular targets modulating the 2008). In another recent study the prognostic value growth inhibitory effects of COX-2 inhibitor NS- of RRM2 was determined in 418 patients with 398 in pancreatic cancer. They found that RRM2 NSCLC who received adjuvant chemotherapy was down-regulated in BxPC-3, MiaPaCa-2 and (Wang et al., 2014). ASPC-1 cell lines after treatment with NS-398. This analysis demonstrated that patients with low Moreover, they identified RRM2 as a biomarker for expression of RRM2 had a significantly higher the chemo-preventive effect of NS-398 in responce to platinum-based chemotherapy (OR = pancreatic cancer cells (Youns et al., 2011). 1.64, 95 % CI = 1.09-2.48) and a longer time to Previous study illustrated that over-expression of progression and overall survival time, with hazard RRM2 was associated with resistance to ratio of 0.57 (0.38-0.86) and 0.47 (0.31-0.71), gemcitabine in pancreatic cancer (Nakano et al., respectively (Wang et al., 2014). 2007). In this study the expression level of RRM2 was analysed by q-PCR in different subclones Breast cancer during the development of acquired resistance to Note gemcitabine. This analysis showed that the It has been shown that RRM2 is overexpressed in expression level of RRM2 enhanced during the human breast carcinoma tissue (DCIS, Jensen et al., development of gemcitabine resistance. Moreover, 1994). Recently Kretschmer and colleagues they also evaluated the expression levels of other identified molecular markers for the ductal genes, RRM1, dCK, hENT1. This results illustrated carcinoma in situ using WAP-TNP8 mouse model. that expression ratio significantly correlated with In particular, they identified seven marker genes gemcitabine sensitivity in eight pancreatic cancer (RRM2, MUC1, SPP1, FOXM1, EXO1, NUSAP1 cell lines, whereas no single gene expression level and DEPDC1), which were overexpressed at a very correlated with the sensitivity, indicating that the early stage of premalignancy and preneoplasia of sensitivity of pancreatic cancer cells to gemcitabine breast carcinomas (Kretschmer et al., 2011). is dependent on the ratio of four factors involved in gemcitabine transport and metabolism. On the one Ovarian cancer hand, the ratio of the four gene expression Note associated with acquired gemcitabine-resistance in Ferrandina and colleagues found a association pancreatic cancer cells (Nakano et al., 2007). between RRM2 expression level and relative risk of Moreover, Duxbury et al., showed that small death in ovarian cancer. interfering RNA targeting RRM2 enhanced In this study they evaluated the mRNA expression chemosensitivity to gemcitabine in pancreatic levels of several genes involved in transportation adenocarcinoma (Duxbury et al., 2004), suggesting and metabolism of gemcitabine, including RRM2, its role as an attractive target for pancreatic cancer. in 25 primary ovarian carcinomas using q-PCR. Lung cancer They showed that samples with high RRM2 expression had a less overall survival, OS, (median Note OS=19 months) with respect to the samples with Several studies have been shown that RRM2 is low RRM2 level (median OS=36 months; overexpressed in lung cancer. In particular, Ferrandina et al., 2010). Souglakos and colleagues showed that patients with low level of RRM2 had a significantly higher Osteosarcoma response rate (60% vs 14.2%), time to progression Note (9.9 vs 2.3 months), and overall survival (15.4 vs Fellenberg et al., in 2007 investigated the 3.6 months) in metastatic lung adenocarcinoma prognostic value of eight genes including RRM2 in patients treated with gemcitabine plus docetaxel 35 formalin-fixed osteosarcoma biopsies. They with respect to the patients with high level of observed a significant relation between RRM2 RRM2 (Souglakos et al., 2008). Furthermore, expression with overall survival of the patients. Boukovinas et al., evaluated the effect of RRM2 However, the prognostic value of this gene did not expression on outcome to gemcitabine plus confirm by multivariate analysis and further studies docetaxel in advanced non-small-cell lung cancer are needed to evaluate the prognostic role of RRM2 (NSCLC) patients. RRM1, RRM2 and BRCA1 in osteosarcoma (Fellenberg et al., 2007).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 35 RRM2 (ribonucleotide reductase M2) Afrasiabi A, et al.

Bladder cancer Parkinson disease Note Note Lu and colleagues investigated whether global gene The inhibitory effect of dopamine on RRM1/2 has expression profiling can help in predecting the been reported in Parkinson disease. Dopamine suitability of rodent models of bladder cancer for inhibits RNR through two pathways: (I) dopamine the detection of cancer-related genes and prediction acts as an effective radical scavenger and scavenge of cancer prevention in human bladder cancer and the tyrosyl radical of RRM2, which is important for carcinogen-induced rodent models. initiating of catalytic process in RRM1 active site They found that 13~34% of whole genome were and (II) chelates the iron center of RRM2 which differentially expressed between tumor and normal acts as a chelator for iron and other metals. In tissues in humans, Fischer-344 rats, and B6D2F1 addition nitric oxide induces dopaminergic mice. neuronal cells through inhibiting RNR (Woldman et Approximately 20% of these differentially al,. 2005; Ebadi and Sharma, 2003). expressed genes overlapped among species, corresponding to 2.6 to 4.8% of whole genes in the To be noted genome. A number of genes were consistently dysregulated Note in bladder tumors in both humans and rodents. This study was supported by grants from CCA Among these genes, RRM2 was up-regulated in Foundation 2012 (Amir Avan), Iranian grant from tumor tissue across three species, suggesting its role Department of New Sciences and Technology, as a potential factor in contributing to bladder School of Medicine, Mashhad University of carcinogenesis (Lu et al., 2010). Medical Sciences, Mashhad, Iran (Amir Avan). Hepatocellular carcinoma References Disease Engström Y, Rozell B. Immunocytochemical evidence for Patients with hepatocellular carcinoma (HCC) the cytoplasmic localization and differential expression suffer from chronic hepatitis or liver cirrhosis. during the cell cycle of the M1 and M2 subunits of Satow and colleagues performed whole-genome mammalian ribonucleotide reductase. EMBO J. 1988 RNA interference-based functional screening in Jun;7(6):1615-20 order to identify genes that sensitize lung cancer Jensen RA, Page DL, Holt JT. Identification of genes cells to drug and genes required for proliferation expressed in premalignant breast disease by microscopy- directed cloning. Proc Natl Acad Sci U S A. 1994 Sep and survival of HCC cells. 27;91(20):9257-61 In this study four genes (AKR1B10, HCAP-G, RRM2, and TPX2) were found to be expressed Goan YG, Zhou B, Hu E, Mi S, Yen Y. Overexpression of ribonucleotide reductase as a mechanism of resistance to strongly in HCC, suggeting their role as potential 2,2-difluorodeoxycytidine in the human KB cancer cell line. therapeutic targets in hepatocellular carcinoma Cancer Res. 1999 Sep 1;59(17):4204-7 (Satow et al., 2010). Park JB, Levine M. Characterization of the promoter of the Gastric cancer human ribonucleotide reductase R2 gene. Biochem Biophys Res Commun. 2000 Jan 19;267(2):651-7 Note Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda Morikawa et al., in 2010, explored the prognostic S, Matsui K, Takei Y, Nakamura Y. A ribonucleotide value of RRM2 in 112 gastric cancer samples using reductase gene involved in a p53-dependent cell-cycle immunohistochemistry (Morikawa et al., 2010). checkpoint for DNA damage. Nature. 2000 Mar They found that RRM2 expression was limited to 2;404(6773):42-9 the neck regions of gastric pits, in normal gastric Eklund H, Uhlin U, Färnegårdh M, Logan DT, Nordlund P. mucosa. Structure and function of the radical enzyme ribonucleotide Moreover, they observed RRM2 overexpression in reductase. Prog Biophys Mol Biol. 2001 Nov;77(3):177-268 72 cases (64.3%), among 112 gastric cancer tissues. Zhou B, Yen Y. Characterization of the human In vitro analysis and inhibition of RRM2 systhesis ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses. Cytogenet Cell Genet. by small interfering RNA, inhibited the growth of 2001;95(1-2):52-9 three gastric cancer cell lines, MKN-1, MKN-7, and SNU-719. Ebadi M, Sharma SK. Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. Furthermore, they demonstarted that Antioxid Redox Signal. 2003 Jun;5(3):319-35 overexpression of RRM2 was associated with the Zhou B, Liu X, Mo X, Xue L, Darwish D, Qiu W, Shih J, gastric cancer progression and suppression of its Hwu EB, Luh F, Yen Y. The human ribonucleotide function could be considered as a potential reductase subunit hRRM2 complements p53R2 in therapeutic strategy in gastric cancer (Morikawa et response to UV-induced DNA repair in cells with mutant al., 2010). p53. Cancer Res. 2003 Oct 15;63(20):6583-94

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 36 RRM2 (ribonucleotide reductase M2) Afrasiabi A, et al.

Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, orthologous gene expression in human bladder cancer and Whang EE. Retrovirally mediated RNA interference carcinogen-induced rodent models. Am J Transl Res. 2010 targeting the M2 subunit of ribonucleotide reductase: A Sep 20;3(1):8-27 novel therapeutic strategy in pancreatic cancer. Surgery. 2004 Aug;136(2):261-9 Morikawa T, Hino R, Uozaki H, Maeda D, Ushiku T, Shinozaki A, Sakatani T, Fukayama M. Expression of Woldman I, Reither H, Kattinger A, Hornykiewicz O, Pifl C. ribonucleotide reductase M2 subunit in gastric cancer and Dopamine inhibits cell growth and cell cycle by blocking effects of RRM2 inhibition in vitro. Hum Pathol. 2010 ribonucleotide reductase. Neuropharmacology. 2005 Dec;41(12):1742-8 Mar;48(4):525-37 Satow R, Shitashige M, Kanai Y, Takeshita F, Ojima H, Nordlund P, Reichard P. Ribonucleotide reductases. Annu Jigami T, Honda K, Kosuge T, Ochiya T, Hirohashi S, Rev Biochem. 2006;75:681-706 Yamada T. Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin Fellenberg J, Bernd L, Delling G, Witte D, Zahlten- Cancer Res. 2010 May 1;16(9):2518-28 Hinguranage A. Prognostic significance of drug-regulated genes in high-grade osteosarcoma. Mod Pathol. 2007 Kretschmer C, Sterner-Kock A, Siedentopf F, Schoenegg Oct;20(10):1085-94 W, Schlag PM, Kemmner W. Identification of early molecular markers for breast cancer. Mol Cancer. 2011 Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura Feb 11;10(1):15 K, Minoguchi M, Izawa T, Mizukami Y, Okumura T, Kohgo Y. Gemcitabine chemoresistance and molecular markers Youns M, Efferth T, Hoheisel JD. Transcript profiling associated with gemcitabine transport and metabolism in identifies novel key players mediating the growth inhibitory human pancreatic cancer cells. Br J Cancer. 2007 Feb effect of NS-398 on human pancreatic cancer cells. Eur J 12;96(3):457-63 Pharmacol. 2011 Jan 10;650(1):170-7 Thelander L. Ribonucleotide reductase and mitochondrial Aimiuwu J, Wang H, Chen P, Xie Z, Wang J, Liu S, DNA synthesis. Nat Genet. 2007 Jun;39(6):703-4 Klisovic R, Mims A, Blum W, Marcucci G, Chan KK. RNA- dependent inhibition of ribonucleotide reductase is a major Boukovinas I, Papadaki C, Mendez P, Taron M, Mavroudis pathway for 5-azacytidine activity in acute myeloid D, Koutsopoulos A, Sanchez-Ronco M, Sanchez JJ, leukemia. Blood. 2012 May 31;119(22):5229-38 Trypaki M, Staphopoulos E, Georgoulias V, Rosell R, Souglakos J. Tumor BRCA1, RRM1 and RRM2 mRNA Bhutia YD, Hung SW, Krentz M, Patel D, Lovin D, expression levels and clinical response to first-line Manoharan R, Thomson JM, Govindarajan R. Differential gemcitabine plus docetaxel in non-small-cell lung cancer processing of let-7a precursors influences RRM2 patients. PLoS One. 2008;3(11):e3695 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein. PLoS One. Souglakos J, Boukovinas I, Taron M, Mendez P, 2013;8(1):e53436 Mavroudis D, Tripaki M, Hatzidaki D, Koutsopoulos A, Stathopoulos E, Georgoulias V, Rosell R. Ribonucleotide Zhou B, Su L, Hu S, Hu W, Yip ML, Wu J, Gaur S, Smith reductase subunits M1 and M2 mRNA expression levels DL, Yuan YC, Synold TW, Horne D, Yen Y. A small- and clinical outcome of lung adenocarcinoma patients molecule blocking ribonucleotide reductase holoenzyme treated with docetaxel/gemcitabine. Br J Cancer. 2008 formation inhibits cancer cell growth and overcomes drug May 20;98(10):1710-5 resistance. Cancer Res. 2013 Nov 1;73(21):6484-93 Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Wang L, Meng L, Wang XW, Ma GY, Chen JH. Expression Ferlini C, Danesi R, Scambia G, Del Tacca M. Expression of RRM1 and RRM2 as a novel prognostic marker in of nucleoside transporters, deoxycitidine kinase, advanced non-small cell lung cancer receiving ribonucleotide reductase regulatory subunits, and chemotherapy. Tumour Biol. 2014 Mar;35(3):1899-906 gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol. 2010 Mar;65(4):679-86 This article should be referenced as such: Lu Y, Liu P, Wen W, Grubbs CJ, Townsend RR, Malone Afrasiabi A, Fiuji F, Mirhafez R, Avan A. RRM2 JP, Lubet RA, You M. Cross-species comparison of (ribonucleotide reductase M2). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):32-37.

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Gene Section Short Communication

YPEL3 (yippee-like 3 (Drosophila)) Gizem Güpür, Mesut Muyan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey (GG, MM)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/YPEL3ID51528ch16p11.html DOI: 10.4267/2042/55376 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Short communication on YPEL3, with data on Description DNA/RNA, on the protein encoded and where the YPEL3 has 4 exons. gene is implicated. Transcription Identity YPEL3 has 2 transcript variants, resulting from the HGNC (Hugo): YPEL3 differential processing of the exon 1. Transcript variant 1: 1588 bp mRNA (NCBI Location: 16p11.2 RefSeq NM_031477.4). Local order: From telomere to centromere: Transcript variant 2: 940 bp mRNA (NCBI RefSeq MAPK3-GDPD3-LOC101928595-YPEL3 -TBX6- NM_001145524.1). PPP4C-ALDOA-FAM57B-C16orf92-DOC2A.

Local order of YPEL3 is shown together with leading and subsequent genes on chromosome 16.

Boxes show exons; filled boxes correspond to coding exons, empty boxes indicate noncoding exons. Lines connecting the boxes represent introns. Arrows indicate the translation initiation codon.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 38 YPEL3 (yippee-like 3 (Drosophila)) Güpür G, Muyan M

Protein follows: C-X2-C-X19 -G-X3-L-X5-N-X13 -G-X8-C- X2-C-X4-GWXY-X10 -K-X6-E. In the consensus Note sequence, the number of non-consensus residues, Two transcript variants encode two protein designated as X, is identical for all species isoforms differing at their amino-termini. examined (Hosono et al., 2004). Protein yippee-like 3 isoform 1; 157 aa protein (NCBI RefSeq NP_113665.3). Implicated in Protein yippee-like 3 isoform 2; 119 aa protein (NCBI RefSeq NP_001138996.1). Colon cancer Expression Note YPEL3 is found to be down-regulated in 9 In human, YPEL3 is expressed in the brain, heart, commercial colon tumor samples and in 22 patient kidney, lung, pancreas, placenta, skeletal muscle, colon adenocarcinoma (Tuttle et al., 2011). colon, ovary, leukocyte, prostate, small intestine, spleen, testis, thymus, bone marrow, leukocyte, Ovarian cancer tonsil, fetal brain, fetal heart, fetal kidney, fetal Note liver, fetal lung, fetal skeletal muscle, fetal spleen A significant decrease in YPEL3 mRNA levels was and fetal thymus (Hosono et al., 2004). detected in 9 commercial and 30 patient ovarian Localisation tumors. In Cp70 ovarian cells, hypermethylation of a CpG island immediately upstream of the YPEL3 Immunofluorescence staining with an antibody promoter is suggested to be the basis for the recognizing Ypel1, 2, 3 and 4 proteins suggests that observed down-regulation (Kelley et al., 2010). Ypel1-4 are nuclear proteins. In interphase cells, Ypel1-4 are localized in nucleoli and the Lung cancer centrosome. In the mitotic phase, Ypel1-4 become Note localized on or close to the mitotic apparatus rather YPEL3 mRNA is shown to be down-regulated in 8 than in the centrosome (Hosono et al., 2004). of 9 commercial lung tumor samples (Tuttle et al., Function 2011). Studies show that the expression of YPEL3 gene is Breast cancer up-regulated during DNA damage, reflected as an increase in YPEL protein levels, likely through two Note functional p53 binding sites present on the YPEL3 YPEL3 is observed to be down-regulated in breast gene promoter (Kelley et al., 2010). cancer cell models. Decrease in YPEL3 mRNA When YPEL3 is expressed by a tetracycline levels by siRNA causes an increase in the growth of inducible system at levels comparable to estrogen receptor positive (ER+) MCF7 cells while endogenous mRNA levels detected upon DNA YPEL3 over-expression decreases cell number. damage, both MCF7 and U2OS cells showed fewer Moreover, YPEL3 mRNA as well as Ypel protein colonies compared to uninduced cells. YPEL3 levels show an increase in MCF7 cells when 17 β- expressing U2OS and MCF7 cells also showed an estradiol (E2) is withdrawn. In contrast, the increase in cellular senescence as shown by addition of E2 at a circulating level (1nM) increases β-galactosidase activity and the decreases the expression of YPEL3. The down- appearance of foci within the nuclei of senescent regulation of YPEL3 by E2 can be reversed by the cells (SAHF) (Kelley et al., 2010). addition of selective estrogen receptor modulator, tamoxifen, TMX (Tuttle et al., 2012). Homology In addition to p53, E2-ER signaling plays a role in In human, YPEL3 has 4 paralogs; YPEL1, YPEL2, the regulation of YPEL3 gene expression based on YPEL4 and YPEL5. Ypel3 has 88.2% aminoacid the observations that the reduction of intracellular sequence identity with Ypel1; 89.1% with Ypel2; ERa levels in MCF7 cells by ERa knockdown 83.9% with Ypel4 and 43.8% with Ypel5 (Hosono increases the expression of YPEL3 gene (Tuttle et et al., 2004). al., 2012). Ypel3 is an ortholog of Drosophila Yippee protein Studies also showed that when grown in the and has 45.5% aminoacid sequence identity to absence of E2, MCF7 cells undergo cellular Yippee. There are 100 YPEL family genes in 68 senescence, whereas the silencing of YPEL3 species including mammal, bird, amphibia, fish, rescues cells from senescence. Further evidence that protochordate, insect, nematode, coelenterate, YPEL3 is involved in E2-ER mediated cellular echinoderm, protozoan, plant, and fungi. In this senescence was obtained from studies showing that diverge range of organisms, YPEL family proteins the treatment of MCF7 cells with TMX increases show a high level of homology with many identical the expression of the YPEL3 gene and that TMX- residues. Thus, a consensus sequence is deduced as induced cellular senescence is not observed when

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 39 YPEL3 (yippee-like 3 (Drosophila)) Güpür G, Muyan M

YPEL3 is silenced. Importantly, cellular senescence Berberich SJ. YPEL3, a p53-regulated gene that induces induced by removal of E2 and/or over-expression cellular senescence. Cancer Res. 2010 May 1;70(9):3566- 75 of YPEL3 is independent of p53 expression. Thus, it appears that YPEL3 plays a role in E2-ER Tuttle R, Simon M, Hitch DC, Maiorano JN, Hellan M, Ouellette J, Termuhlen P, Berberich SJ. Senescence- signaling dependent cellular growth and senescence associated gene YPEL3 is downregulated in human colon in MCF7 cells. tumors. Ann Surg Oncol. 2011 Jun;18(6):1791-6 This in turn implies that Ypel3 is a tumor Tuttle R, Miller KR, Maiorano JN, Termuhlen PM, Gao Y, suppressor protein (Tuttle et al., 2012). Berberich SJ. Novel senescence associated gene, YPEL3, is repressed by estrogen in ER+ mammary tumor cells and References required for tamoxifen-induced cellular senescence. Int J Cancer. 2012 May 15;130(10):2291-9 Hosono K, Sasaki T, Minoshima S, Shimizu N. Identification and characterization of a novel gene family This article should be referenced as such: YPEL in a wide spectrum of eukaryotic species. Gene. 2004 Sep 29;340(1):31-43 Güpür G, Muyan M. YPEL3 (yippee-like 3 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):38- Kelley KD, Miller KR, Todd A, Kelley AR, Tuttle R, 40.

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Gene Section Short Communication

YPEL5 (yippee-like 5 (Drosophila)) Gizem Güpür, Mesut Muyan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey (GG, MM)

Published in Atlas Database: April 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/YPEL5ID44614ch2p23.html DOI: 10.4267/2042/55377 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Reference Sequence: NM_001127399.1). Abstract Transcript variant 4: 2281 bp mRNA (NCBI Review on YPEL5, with data on DNA/RNA, on the Reference Sequence: NM_016061.2). protein encoded and where the gene is implicated. Protein Identity Description Other names: CGI-127 All 4 transcript variants code for the same protein. HGNC (Hugo): YPEL5 Protein yippee-like 5 [Homo sapiens] (NCBI Location: 2p23.1 Reference Sequence: NP_001120873.1); 121 aa protein. Local order From centromere to telomere: FAM179A-C2orf71- Expression CLIP4-ALK-LOC101929418-YPEL5 -LBH- In human, YPEL5 is expressed in the brain, heart, LOC102723594-LOC285043. kidney, lung, pancreas, placenta, skeletal muscle, colon, ovary, leukocyte, prostate, small intestine, DNA/RNA spleen, testis, thymus, bone marrow, leukocyte, tonsil, fetal brain, fetal heart, fetal kidney, fetal Description liver, fetal lung, fetal skeletal muscle, fetal spleen YPEL5 has 5 exons. and fetal thymus (Hosono et al., 2004). Transcription Localisation YPEL5 has 4 transcript variants. Localized in the nucleus in a diffuse pattern, Ypel5 Transcript variant 1: 2639 bp mRNA (NCBI re-localizes in a region between two spindle poles, Reference Sequence: NM_001127401.1). likely on the mitotic spindle during mitosis, Transcript variant 2: 2578 bp mRNA (NCBI suggesting a possible role in cell division (Hosono Reference Sequence: NM_001127400.1). et al., 2004). Ypel5 is localized in the nucleus and Transcript variant 3: 2342 bp mRNA (NCBI on the centrosome during interphase.

Local order of YPEL5 is shown together with leading and subsequent genes on chromosome 2.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 41 YPEL5 (yippee-like 5 (Drosophila)) Güpür G, Muyan M

Boxes show exons; filled boxes correspond to coding exons, empty boxes indicate noncoding exons. Lines connecting the boxes represent introns.

At prophase, it is detected at spindle poles, while Ypel5 is an ortholog of Drosophila Yippee protein during metaphase and early anaphase it becomes and has 70.8% aminoacid sequence identity to associated with mitotic spindle. At mid-anaphase Yippee. There are 100 YPEL family genes in 68 and telophase it is localized in the spindle midzone. species including mammal, bird, amphibia, fish, During cytokinesis, Ypel5 is observed only on the protochordate, insect, nematode, coelenterate, midbody (Hosono et al., 2010). echinoderm, protozoan, plant, and fungi. In this Function diverge range of organisms, YPEL family proteins shows a high level of homology with many Knock-down of YPEL5 in Cos7 cells results in the identical residues. Thus, a consensus sequence is suppression of cell growth by extending durations deduced as follows: C-X2-C-X19 -G-X3-L-X5-N-X13 - of G1 and G2+M phases. Ypel5 was shown to G-X8-C-X2-C-X4-GWXY-X10 -K-X6-E. In the interact, yet by an unknown mechanism, with Ran consensus sequence, the number of non-consensus binding protein in the microtubule organizing residues, designated as X, is identical for all species center (RanBPM) through SPRY domain of examined (Hosono et al., 2004). RanBPM. Ypel5 could also bind RanBP10, paralog of RanBPM. Ypel5 is suggested to function in cell Implicated in division and cell cycle progression through interactions with RanBPM and RanBP10 (Hosono Lung cancer et al., 2010). Note Furthermore, knockdown of YPEL5 homolog Ypel- Treatment of A549 human non-small cell lung b in medaka fish causes a malformation in embryos. carcinoma cell line with ethanolic extract of Normal embryogenesis is interrupted in these Descurainia sophia seeds causes a dose dependent embryos as a result of suppression of cell up-regulation in YPEL5 mRNA levels (Kim et al., proliferation and induction of apoptosis (Hosono et 2013). al., 2010). YPEL5 is expressed in human peripheral T cells in Prognosis G0 stage and it is down-regulated upon activation YPEL5 is found to be related to survival in lung by immobilized anti-CD3. In addition, transfection cancer patients with a hazard ratio of 0.62 (Kim et of YPEL5 into HeLa cells causes a decrease in al., 2013). cellular proliferation (Jun et al., 2007). Chronic lymphocytic leukemia (CLL) Homology Abnormal protein In human, YPEL5 has 4 paralogs; YPEL1, YPEL2, Reciprocal RNA chimeras of YPEL5 and PPP1CB YPEL3 and YPEL4. Ypel5 has 49.5% aminoacid genes are recurrently and exclusively detected in sequence identity with Ypel1; 48.5% with Ypel2; chronic lymphocytic leukemia. YPEL5/PPP1CB 43.8% with Ypel3 and 44.6% with Ypel4 (Hosono and PPP1CB/YPEL5 chimeras form as a result of et al., 2004). an intergenic splicing event and there is no genomic

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 42 YPEL5 (yippee-like 5 (Drosophila)) Güpür G, Muyan M

basis for this fusion which marks a possible Hosono K, Noda S, Shimizu A, Nakanishi N, Ohtsubo M, breakpoint. Shimizu N, Minoshima S.. YPEL5 protein of the YPEL gene family is involved in the cell cycle progression by YPEL5/PPP1CB RNA chimera results in the interacting with two distinct proteins RanBPM and formation of a truncated PPP1CB protein which RanBP10. Genomics. 2010 Aug;96(2):102-11. doi: shows a decreased phosphatase activity. 10.1016/j.ygeno.2010.05.003. Epub 2010 May 24. This RNA chimeric fusion product acts a dominant Kim BY, Lee J, Park SJ, Bang OS, Kim NS.. Gene negative protein that inhibits the function of wild Expression Profile of the A549 Human Non-Small Cell type PPP1CB protein. Lung Carcinoma Cell Line following Treatment with the Seeds of Descurainia sophia, a Potential Anticancer Drug. This results in an enhanced proliferation and colony Evid Based Complement Alternat Med. 2013;2013:584604. formation in B-CLL-related cells (Velusamy et al., doi: 10.1155/2013/584604. Epub 2013 Jun 27. 2013). Velusamy T, Palanisamy N, Kalyana-Sundaram S, Sahasrabuddhe AA, Maher CA, Robinson DR, Bahler DW, References Cornell TT, Wilson TE, Lim MS, Chinnaiyan AM, Elenitoba- Johnson KS.. Recurrent reciprocal RNA chimera involving Hosono K, Sasaki T, Minoshima S, Shimizu N. YPEL5 and PPP1CB in chronic lymphocytic leukemia. Identification and characterization of a novel gene family Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3035-40. YPEL in a wide spectrum of eukaryotic species. Gene. doi: 10.1073/pnas.1214326110. Epub 2013 Feb 4. 2004 Sep 29;340(1):31-43 Jun DY, Park HW, Kim YH.. Expression of Yippee-Like 5 This article should be referenced as such: (YPEL5) Gene During Activation of Human Peripheral T Güpür G, Muyan M. YPEL5 (yippee-like 5 (Drosophila)). Lymphocytes by Immobilized Anti-CD3. Journal of Life Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):41- Science. 2007;17(12): 1641-8. 43.

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Gene Section Review

PML (promyelocytic leukemia) Andrea Rabellino, Pier Paolo Scaglioni Division of Hematology and Oncology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA (AR, PPS)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/PMLID41.html DOI: 10.4267/2042/55378 This article is an update of : Viguié F. PML (Promyelocytic leukemia). Atlas Genet Cytogenet Oncol Haematol 2000;4(4):193-194.

Abstract DNA/RNA Review on PML, with data on DNA/RNA, on the Description protein encoded and where the gene is implicated. PML is composed of 9 exons. Exons 7 and 8 can be Identity divided into exons 7a, 7b, 8a and 8b. Transcription Other names: MYL, RNF71, TRIM19 Transcription of PML generates 22 transcripts HGNC (Hugo): PML (splice variants) with at least 11 different isoforms Location: 15q24.1 (PMLI, PMLIa, PMLII, PMLIIa, PMLIII, PMLIV, PMLIVa, PMLV, PMLVI, PMLVIIa, PMLVIIb). Names of PML isoforms are based on the original nomenclature defined by Jensen et al., 2001. Pseudogene No pseudogenes have been reported so far. Protein Description Alternative splicing of PML gives rise to several isoforms with different molecular weight: PMLI is the longest isoform and is composed of 882 amino acids, while the shortest is PMLVIIb (435 amino acids). PML belongs to the family of the tripartite motif (TRIM). The RBCC/TRIM motif is present in all PML isoforms and is encoded by the exons 1-3. The RBCC domain is composed of a RING finger domain (R), two B-boxes domains (B1 and B2) and an α-helical coiled-coil domain (CC). Top: Courtesy Mariano Rocchi, Resources for Molecular The RING finger motif is a conserved cysteine-rich Cytogenetics. Bottom: Metaphase FISH analysis of PML (green); red dots indicate centromere of chromosome 15 zinc-binding domain found in several classes of (Subramaniyam et al., 2006). proteins.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 44 PML (promyelocytic leukemia) Rabellino A, Scaglioni PP

Structural organization of PML human gene (Nisole et al., 2013).

Schematic representation of PML isoforms (Nisole et al., 2013).

The RING domain of PML is involved in the post-translational modification of PML. Both formation of the PML nuclear bodies (PML-NBs, SUMO1 and SUMO2/SUMO3 bind covalently to see below) and in several others PML functions. PML. SUMOylation facilitates PML-NBs Adjacent to the RING domain lay two cysteine-rich formation promoting tumor suppressive response domains named B-boxes: these two domains have PML-dependent, but also promotes leukemogenesis been proposed to work as second zinc-binding by the SUMOylation of PML-RARA. Finally, domain and they are involved in PML-NBs SUMOylation also promotes ubiquitin-mediate formation and in several others PML functions. The degradation of PML and PML-RARA (Fu et al., coiled-coil domain mediate PML homo- and hetero- 2005; Shen et al., 2006; Lallemand-Breitenbach et dimerization. The CC domain is also essential for al., 2008; Kamitani et al., 1998a; Kamitani et al., PML-NBs formation and PML functions. A nuclear 1998b; Rabellino et al., 2012). Ubiquitination localization signal (NLS) is present in the isoforms regulates PML functions and activity and but not in PMLVIIb. The SUMO interacting motif deregulation of PML appears to be the common (SIM) of PML is required for the recognition and mechanism accounting for PML loss in tumors binding of SUMOylated proteins (Jensen et al., (reviewed in Rabellino and Scaglioni, 2013). 2001; Nisole et al., 2013). The SIM domain also Finally, PML can be also acetylated (Hayakawa et contains the PML degron, involved in the CK2- al., 2008). dependent PML degradation (Scaglioni et al., PML is the major constituent of the PML-NBs. 2006). PML undergoes several post-translational PML-NBs are highly dynamic nuclear structures modifications. Several kinases phosphorylate PML tightly bound to the nuclear matrix. Several on serine and threonine residues regulating its functions of PML are related to the PML-NBs functions (Bernardi et al., 2004; Hayakawa and functions (reviewed in Bernardi et al., 2007). More Privalsky, 2004; Scaglioni et al., 2006; Yang et al., than 150 different proteins have been shown to 2006). SUMOylation is the most intensely studied localize into PML-NBs (Van Damme et al., 2010).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 45 PML (promyelocytic leukemia) Rabellino A, Scaglioni PP

Schematic representation of PML isoform IV protein domains. R = RING-finger domains, aa 55-91; B1, B2 = B-boxes 1 aa 124- 166 and 2 aa 184-228; CC = α-helical coiled-coil domain, aa 233-360; N = nuclear localization signal, aa 428-442; SIM = SUMO interacting motif, 508-518; D = degron. The three major SUMOylation sites (K60, K160 and K442) are indicated, as well as the major phosphorylation sites (T28, S36, S40, S480, T482, S517).

Expression DNA damage response: several proteins involved in DNA repair have been report to reside into PML- PML is ubiquitously expressed. NBs. Localisation Therefore, PML is also involved in DNA-repair, Nuclear (PMLI-VI) and cytoplasmic (PMLVIIb). even though the mechanisms are still not completely clear (reviewed in Dellaire and Bazett- Function Jones, 2004). PML has been implicated in several cellular Anti-viral response: several viral proteins interact functions. with PML and the PML-NBs; moreover, several Cellular senescence: PML is a key regulator of reports implicate PML and PML-NBs in anti-viral cellular senescence. PML is involved in oncogenic- response (reviewed in Geoffroy and Chelbi-Alix, induced senescence (OIS) K-RAS dependent in a 2011). p53 dependent way (de Stanchina et al., 2004; Hematopoietic stem cell maintenance: PML has Ferbeyre et al., 2000; Pearson et al., 2000; been reported being involved in hematopoietic stem Scaglioni et al., 2012). PML is also involved in Rb- cell maintenance by the regulation of the fatty acid dependent senescence (Mallette et al., 2004). oxidation (Ito et al., 2008; Ito et al., 2012). Apoptosis: PML promotes apoptosis primarily by Several functions of PML are related to its ability to its ability to interact with p53 (Wang et al., 1998). form PML-NBs. Moreover, a pro-apoptotic function has been also PML-NBs have been involved in tumor attributed to the cytoplasmic isoform of PML suppression, senescence and apoptosis, DNA- (Giorgi et al., 2010). damage response, cell migration, neoangiogenesis Neoangiogenesis: PML represses HIF1 and anti-viral response (reviewed in Bernardi et al., transcription, blocking de novo angiogenesis 2007). (Bernardi et al., 2006). Cell migration: PML is involved in the regulation Homology of cell migration by the negatively regulating of β-1 PML is conserved in Amniota (source: integrins (Reineke et al., 2010). HomoloGene).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 46 PML (promyelocytic leukemia) Rabellino A, Scaglioni PP

Schematic representation of the mutations type of human PML found in human tumor samples (source COSMIC).

cells at the promyelocytic stage (de Thé et al., Mutations 2012). APL is a distinct subtype of acute myeloid Note leukemia (AML), is a rare condition though PML-RARA is the product of the chromosomal extremely aggressive and malignant. translocation t(15;17) and it causes acute Clinically, APL symptoms tend to be similar to promyelocytic leukemia (APL) (de Thé et al., 1990; AML. APL is characterized by a severe Goddard et al., 1991; Kakizuka et al., 1991; coagulopathy, including disseminated intravascular Pandolfi et al., 1991). coagulation (DIC). Germinal Prognosis APL is normally treated with the combination of No germinal mutations of PML have been reported. retinoic acid (ATRA) and arsenic trioxide (ATO). Somatic This therapy leads to the remission of the disease in At least 65 different somatic mutations have been more than 90% of the cases. Notably, APL was the described. All the informations in this regard can be first malignant disease cured with targeted therapy found at the COSMIC website. (Lo-Coco et al., 2013). B-cell acute lymphoblastic leukemia Implicated in (B-ALL) Acute promyelocytic leukemia (APL) Note Note (Nebral et al., 2007; Qiu et al., 2011; Kurahashi et (de Thé et al., 1990; Goddard et al., 1991; Kakizuka al., 2011) et al., 1991; Pandolfi et al., 1991) Disease Disease The transcription factor PAX5 is required for The balanced chromosomal translocation development and maintenance of B-cell. Several t(15;17)(q24;q21) causes APL by driving the chromosomal translocations involving PAX5 have synthesis of the PML-RARA oncoprotein. This been described, including the t(9;15)(p13;q24) in translocation drives the production of three which the 5' region of PAX5 is fused to PML. So different PML-RARA variants, depending on the far, two cases of B-ALL PAX5-PML-dependent length of the PML module: a short variant PML(S)- have been reported. The fused PAX5-PML RARA, an intermediate variant PML(V)-RARA oncoprotein has a dominant-negative effect on both and a long variant PML(L)-RARA. Generally, 70% PML and PAX5, inhibiting PAX5 activation of B- of the APL patients carry the PML(L)-RARA cell specific genes and disrupting PML-NBs variant, followed by the PML(S)-RARA variant formation. (20%) and the PML(V)-RARA (10%) (Melnick and Prognosis Licht, 1999). PML staining in APL cells show a Kurahashi and colleagues suggest that B-ALL characteristic pattern commonly named PAX5-PML dependent could be treated with ATO "microspeckles" due to the fact that PML-RARA (Kurahashi et al., 2011). disrupts the PML-NBs. PML-RARA acts as a transcriptional repressor of RARA target genes. At Various cancers the same time PML-RARA physically interacts Note with PML, impairing its tumor-suppressive Several reports indicate a reduced PML expression functions. Combined, these features lead to the in several cancer types (Gurrieri et al., 2004; aberrant self-renewal of hematopoietic stem cells Rabellino et al., 2012; Rabellino and Scaglioni, and block of differentiation of myeloid precursor 2013).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 47 PML (promyelocytic leukemia) Rabellino A, Scaglioni PP

Disease Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. PML protein expression was reduced or abolished Chromosomal translocation t(15;17) in human acute in prostate adenocarcinomas (63% [95% confidence promyelocytic leukemia fuses RAR alpha with a novel interval {CI} = 48% to 78%] and 28% [95% CI = putative transcription factor, PML. Cell. 1991 Aug 13% to 43%], respectively), colon adenocarcinomas 23;66(4):663-74 (31% [95% CI = 22% to 40%] and 17% [95% CI = Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, 10% to 24%]), breast carcinomas (21% [95% CI = LoCoco F, Grignani F, Pelicci PG. Structure and origin of 8% to 34%] and 31% [95% CI = 16% to 46%]), the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and lung carcinomas (36% [95% CI = 15% to 57%] and transactivation properties. Oncogene. 1991 Jul;6(7):1285- 21% [95% = 3% to 39%]), lymphomas (14% [95% 92 CI = 10% to 18%] and 69% [95% CI = 63% to Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani 75%]), CNS tumors (24% [95% CI = 13% to 35%] T, Yeh ET. Identification of three major sentrinization sites and 49% [95% CI = 36% to 62%]), and germ cell in PML. J Biol Chem. 1998a Oct 9;273(41):26675-82 tumors (36% [95% CI = 24% to 48%] and 48% Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh [95% CI = 36% to 60%]) but not in thyroid or ET. Covalent modification of PML by the sentrin family of adrenal carcinomas (Gurrieri et al., 2004). In all the ubiquitin-like proteins. J Biol Chem. 1998b Feb cases, PML mRNA levels are comparable to the 6;273(6):3117-20 healthy tissues and the PML gene is rarely mutated, Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, but the protein levels of PML are reduced. This Rivi R, Pandolfi PP. PML is essential for multiple apoptotic correlates with several reports that underline the pathways. Nat Genet. 1998 Nov;20(3):266-72 role of PML degradation in tumor progression and Melnick A, Licht JD. Deconstructing a disease: RARalpha, maintenance (reviewed in Rabellino and Scaglioni, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999 May 2013). 15;93(10):3167-215 Prognosis Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives In most of the cases, loss of PML is associated with C, Lowe SW. PML is induced by oncogenic ras and tumor progression, like was reported for prostate promotes premature senescence. Genes Dev. 2000 Aug cancer, breast cancer and CNS tumors (Gurrieri et 15;14(16):2015-27 al., 2004). Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG. PML regulates p53 acetylation and premature Breakpoints senescence induced by oncogenic Ras. Nature. 2000 Jul Note 13;406(6792):207-10 Breakpoint at q24, responsible of translocation Jensen K, Shiels C, Freemont PS. PML protein isoforms t(15;17)(q24;q21). and the RBCC/TRIM motif. Oncogene. 2001 Oct 29;20(49):7223-33 References Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP. PML regulates p53 stability by de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004 The t(15;17) translocation of acute promyelocytic Jul;6(7):665-72 leukaemia fuses the retinoic acid receptor alpha gene to a de Stanchina E, Querido E, Narita M, Davuluri RV, novel transcribed locus. Nature. 1990 Oct Pandolfi PP, Ferbeyre G, Lowe SW. PML is a direct p53 11;347(6293):558-61 target that modulates p53 effector functions. Mol Cell. Goddard AD, Borrow J, Freemont PS, Solomon E. 2004 Feb 27;13(4):523-35 Characterization of a zinc finger gene disrupted by the Dellaire G, Bazett-Jones DP. PML nuclear bodies: t(15;17) in acute promyelocytic leukemia. Science. 1991 dynamic sensors of DNA damage and cellular stress. Nov 29;254(5036):1371-4 Bioessays. 2004 Sep;26(9):963-77

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Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, modulating calcium release. Science. 2010 Nov Rush LJ, Verbel DA, Cordon-Cardo C, Pandolfi PP. Loss 26;330(6008):1247-51 of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst. 2004 Feb Reineke EL, Liu Y, Kao HY. Promyelocytic leukemia 18;96(4):269-79 protein controls cell migration in response to hydrogen peroxide and insulin-like growth factor-1. J Biol Chem. Hayakawa F, Privalsky ML. Phosphorylation of PML by 2010 Mar 26;285(13):9485-92 mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell. 2004 Van Damme E, Laukens K, Dang TH, Van Ostade X. A Apr;5(4):389-401 manually curated network of the PML nuclear body interactome reveals an important role for PML-NBs in Mallette FA, Goumard S, Gaumont-Leclerc MF, Moiseeva SUMOylation dynamics. Int J Biol Sci. 2010 Jan O, Ferbeyre G. Human fibroblasts require the Rb family of 12;6(1):51-67 tumor suppressors, but not p53, for PML-induced senescence. Oncogene. 2004 Jan 8;23(1):91-9 Geoffroy MC, Chelbi-Alix MK. Role of promyelocytic leukemia protein in host antiviral defense. J Interferon Fu C, Ahmed K, Ding H, Ding X, Lan J, Yang Z, Miao Y, Cytokine Res. 2011 Jan;31(1):145-58 Zhu Y, Shi Y, Zhu J, Huang H, Yao X. Stabilization of PML nuclear localization by conjugation and oligomerization of Kurahashi S, Hayakawa F, Miyata Y et al.. PAX5-PML acts SUMO-3. Oncogene. 2005 Aug 18;24(35):5401-13 as a dual dominant-negative form of both PAX5 and PML. Oncogene. 2011 Apr 14;30(15):1822-30 Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Qiu JJ, Chu H, Lu X, Jiang X, Dong S. The reduced and Pandolfi PP. PML inhibits HIF-1alpha translation and altered activities of PAX5 are linked to the protein-protein neoangiogenesis through repression of mTOR. Nature. interaction motif (coiled-coil domain) of the PAX5-PML 2006 Aug 17;442(7104):779-85 fusion protein in t(9;15)-associated acute lymphocytic leukemia. Oncogene. 2011 Feb 24;30(8):967-77 Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B, Teruya-Feldstein J, Tempst P, de Thé H, Le Bras M, Lallemand-Breitenbach V. The cell Pandolfi PP. A CK2-dependent mechanism for degradation biology of disease: Acute promyelocytic leukemia, arsenic, of the PML tumor suppressor. Cell. 2006 Jul and PML bodies. J Cell Biol. 2012 Jul 9;198(1):11-21 28;126(2):269-83 Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP. Schafer ZT, Evans RM, Suda T, Lee CH, Pandolfi PP. A The mechanisms of PML-nuclear body formation. Mol Cell. PML–PPAR-δ pathway for fatty acid oxidation regulates 2006 Nov 3;24(3):331-9 hematopoietic stem cell maintenance. Nat Med. 2012 Sep;18(9):1350-8 Subramaniyam S, Nandula SV, Nichols G, Weiner M, Satwani P, Alobeid B, Bhagat G, Murty VV. Do RARA/PML Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi fusion gene deletions confer resistance to ATRA-based A, Byers LA, Heymach JV, Girard L, Chiang CM, Teruya- therapy in patients with acute promyelocytic leukemia? Feldstein J, Scaglioni PP. The SUMO E3-ligase PIAS1 Leukemia. 2006 Dec;20(12):2193-5 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res. 2012 May Yang S, Jeong JH, Brown AL, Lee CH, Pandolfi PP, 1;72(9):2275-84 Chung JH, Kim MK. Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. J Biol Scaglioni PP, Rabellino A, Yung TM, Bernardi R, Choi S, Chem. 2006 Sep 8;281(36):26645-54 Konstantinidou G, Nardella C, Cheng K, Pandolfi PP. Translation-dependent mechanisms lead to PML Bernardi R, Pandolfi PP. Structure, dynamics and upregulation and mediate oncogenic K-RAS-induced functions of promyelocytic leukaemia nuclear bodies. Nat cellular senescence. EMBO Mol Med. 2012 Jul;4(7):594- Rev Mol Cell Biol. 2007 Dec;8(12):1006-16 602 Nebral K, König M, Harder L, Siebert R, Haas OA, Strehl Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, S. Identification of PML as novel PAX5 fusion partner in Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, childhood acute lymphoblastic leukaemia. Br J Haematol. Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui 2007 Oct;139(2):269-74 E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T. Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Acetylation of PML is involved in histone deacetylase Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, inhibitor-mediated apoptosis. J Biol Chem. 2008 Sep Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, 5;283(36):24420-5 Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Ehninger G, Schlenk RF, Platzbecker U. Retinoic acid and Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi arsenic trioxide for acute promyelocytic leukemia. N Engl J PP. PML targeting eradicates quiescent leukaemia- Med. 2013 Jul 11;369(2):111-21 initiating cells. Nature. 2008 Jun 19;453(7198):1072-8 Nisole S, Maroui MA, Mascle XH, Aubry M, Chelbi-Alix Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr MK. Differential Roles of PML Isoforms. Front Oncol. R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de Thé H. 2013;3:125 Arsenic degrades PML or PML-RARalpha through a Rabellino A, Scaglioni PP. PML Degradation: Multiple SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Ways to Eliminate PML. Front Oncol. 2013;3:60 Cell Biol. 2008 May;10(5):547-55 Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, This article should be referenced as such: Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Rabellino A, Scaglioni PP. PML (promyelocytic leukemia). Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):44- PML regulates apoptosis at endoplasmic reticulum by 49.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 49

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Short Communication

SOCS6 (suppressor of cytokine signaling 6) Julhash U Kazi, Amilcar Flores-Morales, Lars Rönnstrand Division of Translational Cancer Research and Lund Stem Cell Center, Lund University, Lund, Sweden (JUK, LR), Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (AFM)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/SOCS6ID42351ch18q22.html DOI: 10.4267/2042/55379 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract HGNC (Hugo): SOCS6 Location: 18q22.2 The suppressor of cytokine signaling (SOCS) family of proteins are well known negative DNA/RNA regulators of cytokine receptors signaling consisting of eight structurally similar proteins, Description SOCS1-7 and CIS. A key feature of this family of According to Entrez-Gene SOCS6 maps to proteins is the presence of two structural motifs: a NC_000018.10 in the region between 70288901 centrally located SH2 domain and a SOCS box in and 70330199 on the plus strand. According to the C-terminus. The SOCS box mediates the UCSC genome browser SOCS6 has two exons, one interaction with the Elongins B and C complex shorter of 190 base pairs and other on of 5656 base while an additional motif mediates its interaction pairs. with Cullin 5 to assemble a Cullin/Ring ubiquitin ligase. In this complex SOCS6 acts as a substrate Transcription recognition subunit through interactions mediated SOCS6 mRNA has 5864 nucleotides by the N-terminus and the SH2 domain. SOCS6 (NM_004232.3). The open reading frame (ORF) interacts with tyrosine kinase receptors FLT3 and c- includes 1608 nucleotides situated in exon 2 KIT and modulate their ubiquitination and function. (Figure 1). Transcription is induced by activation of Keywords certain cytokine receptors and growth factor CIS4; SSI4; CIS-4; SOCS4; STAI4; SOCS-4; receptors. SOCS-6; STATI4; HSPC060. Pseudogene Identity Chromosome 11q14.1 has a SOCS6 pseudogene in between 83789973 and 83791578 spanning 1606 Other names: CIS-4, CIS4, HSPC060, SOCS-4, base pairs. The pseudogene has a 92% sequence SOCS-6, SOCS4, SSI4, STAI4, STATI4 similarity with the SOCS6 gene.

Figure 1: SOCS6 mapped on Human Dec. 2013 (GRCh38/hg38) assembly in chromosome 18: (70288901-70330198) spanning 41298 base pairs using UCSC Genome Browser.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 50 SOCS6 (suppressor of cytokine signaling 6) Kazi JU, et al.

Figure 2: Domain structure of SOCS6 protein, SB stand for SOCS-box.

directing proteins for degradation (Kazi et al., 2014; Protein Zadjali et al., 2011). Description Homology SOCS6 gene is expressed as an approximately 60 Homologous proteins are found in various species kDa protein with calculated isoelectric point 6.83 including monkey, mouse, rat, frog and zebra fish and total charge -0.76 at pH 7. etc. Monkey SOCS6 displays as high as 98% SOCS6 has a still uncharacterized long N-terminal sequence similarity to human SOCS6, while zebra region, an SH2 domain and a C-terminal SOCS-box fish SOCS6 display 68% sequence similarity. In (Figure 2). any case, the SOCS-box sequence is highly The protein is mainly expressed in the cytosol and conserved and maintains a 100% sequence associates with multiple proteins (Bayle et al., similarity. 2004; Bayle et al., 2006; Hwang et al., 2007; Kazi et al., 2012; Zadjali et al., 2011). Mutations Most relevant for SOCS6 function is its capacity to associate with Elongin B and Elongin C and with Note Cullin 5 to assemble a functional E3 ubiquitin In the COSMIC database 52 different SOCS6 ligase complex. mutations have been listed, where 40 mutations are non-synonymous (figure 3), two mutations Expression introduce stop codons at 199 and 328 sites, one SOCS6 is highly to moderately expressed in heart, mutation is reported as a 254A and 255G deletion parathyroid, salivary gland, stomach, thyroid, and the other 9 mutations are synonymous kidney and skeletal muscle tissues. Expression was mutations. also reported in mature hematopoietic cells and melanocyte. Implicated in Localisation Hepatocellular carcinoma SOCS6 predominantly localizes to the cytosol and nucleus (Hwang et al., 2007). The N-terminal Note amino acids 1-210 influence its nuclear localization. SOCS6 expression is significantly reduced in Additionally SOCS6 localizes to the mitochondria hepatocellular carcinoma and lower SOCS6 and probably to the inner-surface of cell membrane correlates with overall and disease free survival (Lin et al., 2013). (Qiu et al., 2013). Function Lung squamous cell carcinoma SOCS6 is involved in protein destabilization and to Note some extent acts as a signaling molecule. The Loss of SOCS6 function is associated with poor presence of multiple domains in SOCS6 protein prognosis in primary lung squamous cell facilitates interaction with multiple signaling carcinoma. Copy number loss and slight hyper- molecules. The SOCS6 SH2 domain associates methylation that was correlated with disease with specific tyrosine phosphorylated proteins and progression was reported in this disease (Sriram et the SOCS-box recruits the ubiquitin machinery al., 2012).

Figure 3: Mutations in SOCS6 protein according to COSMIC database.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 51 SOCS6 (suppressor of cytokine signaling 6) Kazi JU, et al.

Prostate cancer Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. J Biol Chem. 2004 Mar Note 26;279(13):12249-59 The down-regulation of SOCS6 has been reported Bayle J, Lopez S, Iwaï K, Dubreuil P, De Sepulveda P. The in prostate cancer tissues with a higher Gleason E3 ubiquitin ligase HOIL-1 induces the polyubiquitination score, the advanced pathological stage, positive and degradation of SOCS6 associated proteins. FEBS metastasis, and the positive PSA failure suggesting Lett. 2006 May 15;580(11):2609-14 that SOCS6 might be associated with aggressive Hwang MN, Min CH, Kim HS, Lee H, Yoon KA, Park SY, progression of prostate cancer (Zhu et al., 2013). Lee ES, Yoon S. The nuclear localization of SOCS6 requires the N-terminal region and negatively regulates Gastric cancer Stat3 protein levels. Biochem Biophys Res Commun. 2007 Aug 24;360(2):333-8 Note Loss of SOCS6 function has been reported in Lai RH, Hsiao YW, Wang MJ, Lin HY, Wu CW, Chi CW, Li AF, Jou YS, Chen JY. SOCS6, down-regulated in gastric gastric cancer. Allelic loss and promoter hyper- cancer, inhibits cell proliferation and colony formation. methylation occur in this cancer. Ectopic expression Cancer Lett. 2010 Feb 1;288(1):75-85 of SOCS6 led to reduced cell growth and colony Zadjali F, Pike AC, Vesterlund M, Sun J, Wu C, Li SS, formation of gastric cancer cell (Lai et al., 2010). Rönnstrand L, Knapp S, Bullock AN, Flores-Morales A. Structural basis for c-KIT inhibition by the suppressor of Pancreatic cancer cytokine signaling 6 (SOCS6) ubiquitin ligase. J Biol Note Chem. 2011 Jan 7;286(1):480-90 The microRNA miR-424-5p is a suppressor of Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, SOCS6 expression. This microRNA is up-regulated Rönnstrand L. Suppressor of cytokine signaling 6 (SOCS6) in pancreatic cancer resulting in down-regulation of negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. J SOCS6 (Wu et al., 2013). Down-regulation of Biol Chem. 2012 Oct 19;287(43):36509-17 SOCS6 led to increased proliferation, migration and invasion of pancreatic cancer cells suggesting Sriram KB, Larsen JE, Savarimuthu Francis SM, Wright CM, Clarke BE, Duhig EE, Brown KM, Hayward NK, Yang SOCS6 acts as a tumor suppressor in pancreatic IA, Bowman RV, Fong KM. Array-comparative genomic cancer. hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma. Glucose metabolism PLoS One. 2012;7(2):e30398 Note Lin HY, Lai RH, Lin ST, Lin RC, Wang MJ, Lin CC, Lee SOCS6 has been shown to interact with the insulin HC, Wang FF, Chen JY. Suppressor of cytokine signaling receptor (INSR), INSR substrates IRS2 and IRS4, 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation. Cell Death Differ. 2013 Jan;20(1):139- and negatively regulates insulin signaling (Krebs et 53 al., 2002; Mooney et al., 2001). Although these findings suggest that SOCS6 might play a role in Qiu X, Zheng J, Guo X, Gao X, Liu H, Tu Y, Zhang Y. Reduced expression of SOCS2 and SOCS6 in glucose metabolism, mice lacking SOCS6 gene did hepatocellular carcinoma correlates with aggressive tumor not display any significant defects in glucose progression and poor prognosis. Mol Cell Biochem. 2013 metabolism apart from a slight growth retardation Jun;378(1-2):99-106 (Krebs et al., 2002). Wu K, Hu G, He X, Zhou P, Li J, He B, Sun W. MicroRNA- 424-5p suppresses the expression of SOCS6 in pancreatic References cancer. Pathol Oncol Res. 2013 Oct;19(4):739-48 Zhu JG, Dai QS, Han ZD, He HC, Mo RJ, Chen G, Chen Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, YF, Wu YD, Yang SB, Jiang FN, Chen WH, Sun ZL, Zhong Shang Y, Furlanetto RW. Suppressors of cytokine WD. Expression of SOCSs in human prostate cancer and signaling-1 and -6 associate with and inhibit the insulin their association in prognosis. Mol Cell Biochem. 2013 receptor. A potential mechanism for cytokine-mediated Sep;381(1-2):51-9 insulin resistance. J Biol Chem. 2001 Jul 13;276(28):25889-93 Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L. SOCS proteins in regulation of receptor tyrosine kinase Krebs DL, Uren RT, Metcalf D, Rakar S, Zhang JG, Starr signaling. Cell Mol Life Sci. 2014 Sep;71(17):3297-310 R, De Souza DP, Hanzinikolas K, Eyles J, Connolly LM, Simpson RJ, Nicola NA, Nicholson SE, Baca M, Hilton DJ, This article should be referenced as such: Alexander WS. SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth Kazi JU, Flores-Morales A, Rönnstrand L. SOCS6 retardation. Mol Cell Biol. 2002 Jul;22(13):4567-78 (suppressor of cytokine signaling 6). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):50-52. Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P.

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Leukaemia Section Review del(4)(q12q12) FIP1L1/PDGFRA Adriana Zamecnikova, Soad Al Bahar Kuwait Cancer Control Center, Dep of Hematology, Laboratory of Cancer Genetics, Kuwait (AZ, SA)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del4q12q12ID1213.html DOI: 10.4267/2042/55380 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

eosinophils, CD34+ cells, mast cells and even Abstract lymphoid) consistent with an origin in an Review on del(4)(q12q12) FIP1L1/PDGFRA, with hematopoietic stem cells or early progenitors data on clinics, and the genes implicated. progenitor (Gotlib and Cools, 2008). Identity Etiology The cause of FIP1L1-PDGFRA associated Other names hypereosinophilic syndrome is unknown as well as Interstitial 4q12 deletion its association with predominantly male sex. FIP1L1/PDGFRA fusion in eosinophilia-associated hematologic disorders Epidemiology FIP1L1-PDGFRA (+) eosinophilias are considered Clinics and pathology to be rare entities; however the incidence rates for molecularly defined eosinophilic disorders are not Disease known. An interstitial deletion del(4)(q12q12) generating a Data support a FIP1L1-PDGFRA fusion incidence FIP1L1-PDGFRA fusion gene is observed in of approximately 10-20% among patients diverse eosinophilia-associated hematologic presenting with idiopathic hypereosinophilia disorders like hyperseosinophilic syndrome (HES), (Gotlib and Cools, 2008). systemic mastocytosis (SM) and chronic However, in unselected patients with eosinophilia eosinophilic leukemia (CEL). only 3% of were found to carry the FIP1L1- The updated WHO classification distinguishes PDGFRA fusion (Pardanani et al., 2004; Pardanani these myeloid and lymphoid neoplasms with et al., 2006). eosinophilia and abnormalities of PDGFRA, Clinics PDGFRB or FGFR1 as chronic eosinophilic leukemia (CEL) not otherwise specified (NOS); Characteristic feature of PDGFRA-associated lymphocyte-variant hypereosinophilia and disorders is eosinophil overproduction in the bone idiopathic hypereosinophilic syndrome (HES) marrow resulting in increased blood eosinophils. (Gleich and Leiferman, 2009; Gotlib, 2014). Marked and sustained eosinophilia eventually leads Occasionally, the FIP1L1-PDGFRA fusion can be to eosinophilic infiltration and functional damage of identified in patients with acute myeloid leukemia peripheral organs, most commonly the heart, skin, or B-cell or T-cell acute lymphoblastic leukemia or lungs, or nervous system. lymphoblastic lymphoma and sporadically in Patients often present with hepatomegaly or myeloid sarcoma (Metzgeroth et al., 2007; Tang et splenomegaly hypercellular bone marrows with al., 2012). myelofibrosis, increased number of neutrophils and/or mast cells. Phenotype/cell stem origin Serum B12 and tryptase levels may be significantly FIP1L1-PDGFRA rearrangement has been found in elevated (Vandenberghe et al., 2004; Gleich and a variety of cell lineages (neutrophils, monocytes, Leiferman, 2009).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 53 del(4)(q12q12) FIP1L1/PDGFRA Zamecnikova A, Al Bahar S

Figure 1. Detection of the del(4)(q12q12) by fluorescence in situ hybridization using the LSI FIP1L1-CHIC2-PDGFRA Triple- Color, split assay (Abott Molecular; Vysis, Denver US) on a metaphase (A) and interphases (B). This probe is designed as a deletion probe when absence of the CHIC2 region is observed as loss of a red signal (arrows) from the co-localized green/blue signal, indicative of the presence of this specific deletion that leads to FIP1L1-PDGFRA fusion on one of the chromosomes 4.

Treatment Acquired resistance is exceedingly rare; the T674I mutation in the ATP-binding region of PDGFRA FIP1L1-PDGFRA associated hypereosinophilic (mutation of the threonine at position 674) is the disorders are sensitive to treatments with tyrosine most common. Interestingly, the T674I mutation kinase inhibitors such as imatinib mesylate that is analogous to the T315I mutation of BCR- (imatinib). Imatinib is the first-line therapy for ABL1 in chronic myeloid leukemia also confers patients with abnormalities of PDGFRA; however imatinib resistance (Cools et al., 2003; Jain et al., chronic eosinophilic leukemia with FIP1L1- 2013). For refractory disease, interferon-a may be a PDGFRA is likely to be responsive also to therapeutic option. dasatinib, nilotinib, sorafenib and midostaurin (PKC412) (Lierman et al., 2009). Cytogenetics Prognosis Note Patients with hypereosinophilic syndrome The cryptic interstitial deletion on chromosome historically carried a poor prognosis before the band 4q12 leading to FIP1L1-PDGFRA fusion is successful therapeutic application of tyrosine kinase quite unique as it is generated by a cryptic inhibitors. Targeted therapy has dramatically chromosomal deletion, rather than a translocation changed the prognosis of patients carrying the (Gotlib and Cools, 2008). FIP1L1-PDGFRA fusion which show an excellent response to low-dose imatinib. Treatment with low- Cytogenetics morphological dose imatinib (100 mg/d) produced complete and Because FIP1L1-PDGFRA is generated by a durable responses with normalization of cryptic deletion at 4q12 that is only 800 kb in size, eosinophilia. Importantly, these remissions appear it remains undetected with standard cytogenetics. to be durable with continued imatinib therapy in a Therefore; most of the patients with the fusion have high proportion of patients (Barraco et al., 2014). an apparently normal karyotype.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 54 del(4)(q12q12) FIP1L1/PDGFRA Zamecnikova A, Al Bahar S

Figure 2. Model of the involvement of PDGFRA-FIP1L1 fusion gene in the pathogenesis of hypereosinophilic disorders. A cryptic deletion on chromosome 4 brings the normally distant PDGFRA and FIP1L1 genes into close proximity, generating a fused gene. Fusion of FIP1L1 to the PDGFRA protein results in a constitutive kinase activation of PDGFRA with transforming potential that may lead to eosinophilic disorders. Administration of the kinase inhibitor such as imatinib is highly effective molecularly targeted therapy for this group of patients.

Occasional patients have had a chromosomal rearrangement with a 4q12 breakpoint, such as Genes involved and t(1;4)(q44;q12), which ultimately led to the proteins identification of the fusion gene or t(4;10)(q12;p11) (Cools et al., 2003; Gotlib et al., 2004). PDGFRA Cytogenetics molecular Location One of the best techniques to detect the presence of 4q12 the FIP1L1-PDGFRA fusion gene is using triple- Note color FISH probes hybridizing to the region platelet-derived growth factor receptor, alpha between the FIP1L1 and PDGFRA genes polypeptide incorporating the CHIC2 (cysteine-rich DNA/RNA hydrophobic domain 2) gene. PDGFRA contains 23 exons spanning about 65 kb. A more sensitive technique is the use of reverse- The gene encodes a cell surface tyrosine kinase transcription polymerase chain reaction (RT-PCR) receptor. An important paralog of PDGFRA is (La Starza et al., 2005) or quantitative RT-PCR FLT4. methods, used for monitoring therapy response to tyrosine kinase inhibitors. Protein 1089 amino acids; PDGFA belongs to a family of Variants receptor tyrosine kinases that include PDGFRA and A few other variant PDGFRA fusion genes have PDGFRB that have intracellular tyrosine kinase been described: t(4;22)(q12;q11)/BCR-PDGFRA, activity that binds members of the platelet-derived t(2;4)(p24;q12)/STRN-PDGFRA, growth factor family. ins(9;4)(q33;q12q25)/CDK5RAP2-PDGFRA, It plays an essential role in the regulation of complex karyotype/KIF5B-PDGFRA and embryonic development, organ development, t(4;12)(q12;p13)/ETV6-PDGFRA (Gleich and wound healing, angiogenesis and chemotaxis; role Leiferman, 2009). The involvement of FIP1L1 was in the differentiation of bone marrow-derived described in a t(4;17)(q12;q21) with FIP1L1/RARA mesenchymal stem cells, cell proliferation and fusion in a patient with juvenile myelomonocytic survival (Hsieh et al., 1991; Kawagishi et al., leukemia (Shah et al., 2014). 1995).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 55 del(4)(q12q12) FIP1L1/PDGFRA Zamecnikova A, Al Bahar S

Figure 3. Generation of the FIP1L1-PDGFRA fusion protein. Splicing of FIP1L1 exons to the truncated exon 12 of PDGFRA results in disruption of the autoinhibitory juxtamembrane domain of PDGFRA. FIP1L1-PDGFRA expression became under control of the ubiquitous FIP1L1 promoter leading to dysregulated tyrosine kinase activity. NLS indicates nuclear localization signal; TM, transmembrane region; JM, juxtamembrane region. Adapted from Cools et al., 2003; Vandenberghe et al., 2004; Gotlib and Cools, 2008; Gleich and Leiferman, 2009.

PDGFRA is involved in the pathogenesis of various Several genes between FIP1L1 and PDGFRA have disorders, including cancer. been identified: LNX1 (the ligand of numb-protein FIP1L1 X 1), the hypothetical protein LOC402176 (LOC402176), CHIC2 (cysteine-rich hydrophobic Location domain 2) and the homeobox protein GSH-2 4q12 (GSH2). While breakpoints in FIP1L1 are scattered Note over a region of 40 kb (introns 7-10), breakpoints factor interacting with PAPOLA and CPSF1 within the PDGFRA gene are tightly clustered and are always within exon 12, encoding the DNA/RNA juxtamembrane region (JM). Truncations of the JM 4 distinct isoforms; alternative splicing results in region invariably results in the removal of part of multiple transcript variants. the juxtamembrane domain and generation of in- Protein frame fusion transcripts (Cools et al., 2003; pre-mRNA 3'-end-processing factor; 520 amino Vandenberghe et al., 2004). Rarely, FIP1L1 acids. FIP1 belongs to the FIP1 family. It has RNA breakpoint is located outside of the common binding protein kinase activity as a component of FIP1L1 breakpoint regions (Lambert et al., 2007). cleavage and polyadenylation specificity factor Transcript (CPSF) complex. Plays a key role in 5'FIP1L1-3'PDGFRA; no reciprocal PDGFRA- polyadenylation of the 3' end of mRNA precursors FIP1L1 fusion gene can be detected as the fusion is and in the transcriptional process. FIP1L1 is the consequence of an interstitial deletion and not a predicted to be under the control of a ubiquitous reciprocal translocation. promoter. Many additional functions of the protein As the normal splice site at 5' part of exon 12 of are largely unknown (Gotlib et al., 2004). PDGFRA is deleted, cryptic splice sites in FIP1L1 introns or within exon 12 of PDGFRA are used to Result of the chromosomal generate in-frame FIP1L1-PDGFRA fusions anomaly (Gotlib and Cools, 2008). Hybrid gene Fusion protein Description Description In-frame fusion of the 5' part of FIP1L1 to the 3' The FIP1L1-PDGFRA protein is made by the first part of PDGFRA. twelve exons of FIP1L1 and from truncated exon The generation of the fusion between the 5' part of 12 (containing the last 17 amino acids) to exon 23 the FIP1L1 gene and the 3' part of the PDGFRA of PDGFRA. The FIP1L1-PDGFRA fusion protein gene is the consequence of a deletion of the 800 kb is a constitutively activated tyrosine kinase that genomic region between the two genes on 4q12. joins the first 233 amino acids of FIP1L1 to the last

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 56 del(4)(q12q12) FIP1L1/PDGFRA Zamecnikova A, Al Bahar S

523 amino acids of PDGFRA (Gotlib and Cools, clinicopathologic correlates in 89 consecutive patients with 2008). moderate to severe eosinophilia. Blood. 2004 Nov 15;104(10):3038-45 Oncogenesis Vandenberghe P, Wlodarska I, Michaux L, Zachée P, An interstitial deletion on chromosome 4q12 site Boogaerts M, Vanstraelen D, Herregods MC, Van Hoof A, brings the normally distant PDGFRA and FIP1L1 Selleslag D, Roufosse F, Maerevoet M, Verhoef G, Cools genes into proximity generating a hybrid FIP1L1- J, Gilliland DG, Hagemeijer A, Marynen P. Clinical and PDGFRA gene. In the translated protein, the molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia. 2004 Apr;18(4):734-42 juxtamembrane domain of PDGFRA that is known to serve an autoinhibitory function is truncated and La Starza R, Specchia G, Cuneo A, Beacci D, Nozzoli C, Luciano L, Aventin A, Sambani C, Testoni N, Foppoli M, became under control of the ubiquitous FIP1L1 Invernizzi R, Marynen P, Martelli MF, Mecucci C. The promoter resulting in its constitutive kinase hypereosinophilic syndrome: fluorescence in situ activation. Dysregulated tyrosine kinase activity hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but leads to proliferation of multiple myeloid lineages not genomic rearrangements of other tyrosine kinases. via activation of several pathways. The STAT1/3 Haematologica. 2005 May;90(5):596-601 and STAT5 (signal transducers and activators of Pardanani A, Ketterling RP, Li CY, Patnaik MM, Wolanskyj transcription) transcriptional factors appear to be AP, Elliott MA, Camoriano JK, Butterfield JH, Dewald GW, Tefferi A. FIP1L1-PDGFRA in eosinophilic disorders: activated either directly or via interaction with JAK prevalence in routine clinical practice, long-term (Janus activated kinase) pathways. However, the experience with imatinib therapy, and a critical review of exact mechanism, by which FIP1L1-PDGFR affects the literature. Leuk Res. 2006 Aug;30(8):965-70 the development of HES/CEL and why Yamada Y, Rothenberg ME, Lee AW, Akei HS, Brandt EB, preferentially affects eosinophils remains unclear. Williams DA, Cancelas JA. The FIP1L1-PDGFRA fusion Mouse models of FIP1L1-PDGFRA induced gene cooperates with IL-5 to induce murine disease revealed that FIP1L1-PDGFRA expression hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease. Blood. 2006 May induce a myeloproliferative phenotype without 15;107(10):4071-9 eosinophilia. Therefore, it is likely that FIP1L1- Lambert F, Heimann P, Herens C, Chariot A, Bours V. A PDGFRA expression alone is not sufficient to cause case of FIP1L1-PDGFRA-positive chronic eosinophilic eosinophilia and additional processes such as leukemia with a rare FIP1L1 breakpoint. J Mol Diagn. 2007 cooperation with nuclear factor-kB and IL-5 Jul;9(3):414-9 signaling are required in differentiation towards the Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, eosinophil lineage (Yamada et al., 2006; Montano- Haferlach C, Popp H, Haferlach T, Erben P, Mix J, Müller Almendras et al., 2012). MC, Beneke H, Müller L, Del Valle F, Aulitzky WE, Wittkowsky G, Schmitz N, Schulte C, Müller-Hermelink K, Hodges E, Whittaker SJ, Diecker F, Döhner H, Schuld P, Hehlmann R, Hochhaus A, Cross NC, Reiter A. Recurrent References finding of the FIP1L1-PDGFRA fusion gene in eosinophilia- associated acute myeloid leukemia and lymphoblastic T- Hsieh CL, Navankasattusas S, Escobedo JA, Williams LT, cell lymphoma. Leukemia. 2007 Jun;21(6):1183-8 Francke U. Chromosomal localization of the gene for AA- type platelet-derived growth factor receptor (PDGFRA) in Gotlib J, Cools J. Five years since the discovery of humans and mice. Cytogenet Cell Genet. 1991;56(3- FIP1L1-PDGFRA: what we have learned about the fusion 4):160-3 and other molecularly defined eosinophilias. Leukemia. 2008 Nov;22(11):1999-2010 Kawagishi J, Kumabe T, Yoshimoto T, Yamamoto T. Structure, organization, and transcription units of the Gleich GJ, Leiferman KM. The hypereosinophilic human alpha-platelet-derived growth factor receptor gene, syndromes: current concepts and treatments. Br J PDGFRA. Genomics. 1995 Nov 20;30(2):224-32 Haematol. 2009 May;145(3):271-85 Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Lierman E, Michaux L, Beullens E, Pierre P, Marynen P, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Cools J, Vandenberghe P. FIP1L1-PDGFRalpha D842V, a Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose novel panresistant mutant, emerging after treatment of M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska FIP1L1-PDGFRalpha T674I eosinophilic leukemia with I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland single agent sorafenib. Leukemia. 2009 May;23(5):845-51 DG. A tyrosine kinase created by fusion of the PDGFRA Montano-Almendras CP, Essaghir A, Schoemans H, Varis and FIP1L1 genes as a therapeutic target of imatinib in I, Noël LA, Velghe AI, Latinne D, Knoops L, Demoulin JB. idiopathic hypereosinophilic syndrome. N Engl J Med. ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human 2003 Mar 27;348(13):1201-14 hematopoietic progenitor cell proliferation and Gotlib J, Cools J, Malone JM 3rd, Schrier SL, Gilliland DG, differentiation into eosinophils: the role of nuclear factor- Coutré SE. The FIP1L1-PDGFRalpha fusion tyrosine κB. Haematologica. 2012 Jul;97(7):1064-72 kinase in hypereosinophilic syndrome and chronic Tang TC, Chang H, Chuang WY. Complete response of eosinophilic leukemia: implications for diagnosis, myeloid sarcoma with FIP1L1-PDGFRA -associated classification, and management. Blood. 2004 Apr myeloproliferative neoplasms to imatinib mesylate 15;103(8):2879-91 monotherapy. Acta Haematol. 2012;128(2):83-7 Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Jain N, Khoury JD, Pemmaraju N, Kollipara P, Kantarjian Ketterling RP, Lasho TL, Ho CL, Li CY, Dewald GW, H, Verstovsek S. Imatinib therapy in a patient with Tefferi A. FIP1L1-PDGFRA fusion: prevalence and suspected chronic neutrophilic leukemia and FIP1L1-

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PDGFRA rearrangement. Blood. 2013 Nov management. Am J Hematol. 2014 Mar;89(3):325-37 7;122(19):3387-8 Shah S, Loghavi S, Garcia-Manero G, Khoury JD. Barraco D, Carobolante F, Candoni A, Simeone E, Discovery of imatinib-responsive FIP1L1-PDGFRA Piccaluga P, Tabanelli V, Fanin R. Complete and long- mutation during refractory acute myeloid leukemia lasting cytologic and molecular remission of FIP1L1- transformation of chronic myelomonocytic leukemia. J PDGFRA-positive acute eosinophil myeloid leukaemia, Hematol Oncol. 2014 Mar 27;7:26 treated with low-dose imatinib monotherapy. Eur J Haematol. 2014 Jun;92(6):541-5 This article should be referenced as such: Gotlib J. World Health Organization-defined eosinophilic Zamecnikova A, Al Bahar S. del(4)(q12q12) disorders: 2014 update on diagnosis, risk stratification, and FIP1L1/PDGFRA. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):53-58.

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Leukaemia Section Short Communication t(5;9)(q14.1;p24) SSBP2/JAK2 Elizabeth A Morgan, Paola Dal Cin Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA (EAM, PD)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0509q14p24ID1680.html DOI: 10.4267/2042/55381 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Cytogenetics Review on t(5;9)(q14.1;p24) SSBP2/JAK2, with Note data on clinics, and the genes implicated. t(5;9) detected in 19 of 20 GTG-banded metaphase cells analyzed from a 24-hr unstimulated bone Identity marrow culture. Other names Cytogenetics molecular SSBP2-JAK2 fusion The breakpoint on chromosome 9p was found to be distal to band p23 by FISH mapping on abnormal metaphase. The breakpoint was found to reside Clinics and pathology within the JAK2 locus by hybridizing a BAC Disease spanning the JAK2 gene (RP11-927h16; nucleotides 4965192-5138016), which produced B-lymphoblastic leukemia/lymphoma signals on both der(9) and der(5) chromosomes. Phenotype/cell stem origin Additional FISH mapping localized the CD45+(dim), TdT+, CD34+(subset), HLA-DR+, chromosome 5 breakpoint to a 57.5 kb interval at CD19+, CD10+, and CD20+(variable) with weak 5q14.1 spanning SSBP2, with RP11-120L4 aberrant expression of the myeloid markers CD13 (nucleotides 80698679-80848640) and RP11- and CD33; no expression of surface 147O19 (nucleotides 80861153-81023195) flanking immunoglobulin, T lymphoid, and other myeloid the breakpoint; the presence of the SSBP2-JAK2 and monocytic markers. transcript was confirmed by RT-PCR. Epidemiology Additional anomalies One reported case; 39-year-old male presenting With disease progression, a subsequent sample with a white blood cell count of 400x10 9/L with revealed additional chromosome aberrations: 98% blasts (Poitras et al., 2008). 46,XY,t(5;9)(q14.1;p24.1) [cp10]/46,idem, t(1;13)(p22;q32), Treatment t(15;20)(q15;q13)[3]/46,idem,t(1;3)(p36;p21),del(1 Prednisone, vincristine, doxorubicin, asparaginase, 2)(q12q13)[cp7]. and high-dose methotrexate; achieved complete remission after 30 days of cytoreductive Genes involved and chemotherapy; also received prophylactic intrathecal chemotherapy and cranial radiation. proteins Prognosis SSBP2 Rapid systemic relapse; 8 months after initial Location diagnosis the patient died from progressive disease. 5q14.1

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 59 t(5;9)(q14.1;p24) SSBP2/JAK2 Morgan EA, Dal Cin P

a). Partial GTG-banded karyotypes showing the t(5;9)(q14.1;p24.1). b). Partial FISH analysis showing the 5'JAK2 hybridization signal on der(5), the 3'JAK2 hybridization signal on der(9) and an intact JAK2 hybridization signal on the normal chromosome 9.

DNA/RNA and 290 bp; sequencing revealed that each 17 exons. contained the same 3' JAK2 sequences (exon 11 and downstream 3' sequence), but different joining Protein 5' SSBP2 sequences (junction occurred at the 3' end Single-stranded DNA-binding complex; plays role of SSBP2 exons 5, 4, and 3, respectively termed in the maintenance of genome stability. T1-T3). JAK2 Fusion protein Location Description 9p24 It is predicted that T1 and T2, which are both in- DNA/RNA frame, will encode SSBP2-JAK2 fusion proteins 24 exons. containing the SSBP2 Lissencephaly type I-like homology (LisH) motif as well as the JH2 and JH1 Protein domains of JAK2; the T3 fusion is out of frame and Tyrosine kinase; cytokine receptor signaling. may encode a truncated SSBP2 protein with a COOH-terminal deletion of the proline-rich, Result of the chromosomal glycine-rich, and downstream regions. anomaly Oncogenesis Other JAK2 fusions with other partners genes Hybrid gene PCM1 (8p22), BCR (22q11.2) and ETV6 (12p13) lead to dimerization of adjacent, receptor-associated Description JAKs, and ensuing auto- and trans-phosphorylation 5'SSBP2-3'JAK2. causing constitutive kinase activation (Lacronique Transcript et al., 1997); it is predicted that the LisH RT-PCR using the forward primer in exon 3 of (Lissencephaly type I-like homology) motif in SSBP2 and the reverse primer in exon 12 of JAK2 SSBP2 may permit a similar mechanism of JAK2 yielded three discrete products of 465 bp, 375 bp, activation.

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 60 t(5;9)(q14.1;p24) SSBP2/JAK2 Morgan EA, Dal Cin P

To be noted 1;90(7):2535-40 Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Note Mauchauffé M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA. A TEL-JAK2 fusion protein with constitutive JAK2 fusion proteins have been described in kinase activity in human leukemia. Science. 1997 Nov several hematopoietic neoplasms including acute 14;278(5341):1309-12 leukemias and myeloproliferative neoplasms. The Reiter A, Walz C, Watmore A, Schoch C, Blau I, fusion partners reported in B-lineage acute Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, lymphoblastic leukemia (ALL) include ETV6 Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, (Peeters et al., 1997), PCM1 (Reiter et al., 2005), Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann PAX5 (Nebral et al., 2009), BCR and STRN3 R, Chase A, Cross NC. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses (Roberts et al., 2012). It is thought that these PCM1 to JAK2. Cancer Res. 2005 Apr 1;65(7):2662-7 fusions result in constitutive JAK2 tyrosine kinase activity, and it is predicted that patients with B- Poitras JL, Dal Cin P, Aster JC, Deangelo DJ, Morton CC. Novel SSBP2-JAK2 fusion gene resulting from a ALL exhibiting one of these fusions may respond to t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. JAK2 inhibitors (Lacronique et al., 1997; Roberts et Genes Chromosomes Cancer. 2008 Oct;47(10):884-9 al., 2012). This is clinically relevant given that at Nebral K, Denk D, Attarbaschi A, König M, Mann G, Haas least the PAX5-JAK2, BCR-JAK2 and STRN3- OA, Strehl S. Incidence and diversity of PAX5 fusion JAK2 fusions have been associated with a group of genes in childhood acute lymphoblastic leukemia. high-risk B-lineage ALLs known as BCR-ABL1 Leukemia. 2009 Jan;23(1):134-43 negative ALL or "Ph-like ALL", which are Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, characterized by a gene expression profile similar to Chen SC, Payne-Turner D, Churchman ML, Harvey RC, BCR-ABL1-positive ALL, an alteration of IKZF1, Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, and poor prognosis (Roberts et al., 2012). The Mungall K, Birol I, Edmonson MN, Hu Y, Buetow KE, Chen translocation described herein describes an IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia- additional JAK2 fusion protein in B-lineage ALL Manero G, Larsen E, Shah NP, Devidas M, Reaman G, (SSBP2-JAK2) (Poitras et al., 2008). Smith M, Paugh SW, Evans WE, Grupp SA, Jeha S, Pui CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra MA, Mullighan CG. Genetic alterations References activating kinase and cytokine receptor signaling in high- risk acute lymphoblastic leukemia. Cancer Cell. 2012 Aug Peeters P, Raynaud SD, Cools J, Wlodarska I, 14;22(2):153-66 Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P. Fusion of TEL, This article should be referenced as such: the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and Morgan EA, Dal Cin P. t(5;9)(q14.1;p24) SSBP2/JAK2. t(9;15;12) in a myeloid leukemia. Blood. 1997 Oct Atlas Genet Cytogenet Oncol Haematol. 2015; 19(1):59- 61.

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Solid Tumour Section Short Communication

Mesothelioma: t(14;22)(q32;q12) in mesothelioma Ioannis Panagopoulos Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo 031, Norway (IP)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t1422q32q12MesotheliomID6460.html DOI: 10.4267/2042/55382 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Genetic predisposition, smoking, radiation, and Identity viral infection can also contribute to mesothelioma Mesothelioma is an aggressive tumor derived from either alone or together with exposure to asbestos. mesothelial cells. It is primarily found in the pleura Epidemiology (75%), peritoneum (10-20%), pericardium (1%) and tunica vaginalis (< 1%) (Moore et al., 2008). For a detailed and update epidemiology of Mesothelioma is strongly associated with exposure mesothelioma see: to asbestos which can be documented in about 50- http://www.uptodate.com/contents/epidemiology- 80% of pleural cases and 30% of peritoneal of-malignant-pleural-mesothelioma. mesothelioma in men (Bianchi and Bianchi, 2007). Genetic predisposition, smoking, radiation, and Genetics viral infection can also contribute to mesothelioma. Note The onset of mesothelioma is insidious with a Abnormal karyotypes detected by cytogenetic latency of 30 years (range: 20 to 50 years). analysis have been reported in 128 mesotheliomas The mean age of the patients is 60 years, but the (Mitelman database). disease can occur at any age (Moore et al., 2008). The changes are mostly complex, but a number of Survival rates vary but they generally remain low nonrandom abnormalities have been found (Asbestos.com). involving chromosome arms 1p, 3p, 6q, 9p, and 22q. Studies using comparative genomic Clinics and pathology hybridization, loss of heterozygosity, and Disease fluorescence in situ hybridization (FISH) have also shown repeated regional chromosomal gains and Mesothelioma losses. Among them, losses of chromosome bands Phenotype / cell stem origin 14q32 and 22q12 were found in 43-50% and 36% of the cases, respectively (Taniguchi et al., 2007; Mesothelioma is derived from mesothelial cells. Takeda et al., 2012). On band 22q12, the NF2 gene Embryonic origin was found to be mutated in 40% of mesotheliomas Unknown. leading to complete functional inactivation of NF2 (see Thurneysen et al., 2009; and references Etiology therein). In two other studies, NF2 was found to be Mesothelioma is strongly associated with exposure deleted (Taniguchi et al., 2007; Takeda et al., to asbestos which can be documented in about 50- 2012). On chromosome band 14q32, the CHGA 80% of pleural cases and 30% of peritoneal and ITPK1 genes were found to be deleted mesothelioma in men (Bianchi and Bianchi, 2007). (Taniguchi et al., 2007; Takeda et al., 2012).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 62 Mesothelioma: t(14;22)(q32;q12) in mesothelioma Panagopoulos I

A. Fluorescence in situ hybridization using BAC RP11-638I2 (FITC, green) for the YY1 gene (14q32) and RP11-612D3 (Texas Red, red) for the EWSR1 gene (22q12). The fusion signals are seen on both derivative chromosomes. B. Mapping position of the RP11-638I2. C. Mapping position of the RP11-612D3.

Cytogenetics Protein 414 amino acids, 44.7 kDa. Note In a mesothelioma, which was diagnosed as EWSR1 epithelioid type, the G-banding analysis yielded a Location karyotype with only a single chromosomal 22q12.2 abnormality: DNA / RNA 46,XY,t(14;22)(q32;q12)[10]/46,XY[5] Spans 32.5 kb on plus strand. Transcript of 2654 bp (Panagopoulos et al., 2013). from 17 exons for the canonical form, with a coding sequence of 1971 nt. Protein 656 amino acids, 68.5 kDa. Result of the chromosomal anomaly Hybrid Gene Note The balanced 14;22-translocation generates a Partial karyotype showing the two derivative chromosomes, functional EWSR1-YY1 chimeric gene in which der(14)t(14;22)(q22;q12) and der(22)t(14;22)(q22;q12), from the 14;22 translocation together with their exon 8 of EWSR1 (nucleotide 1139 accession corresponding normal homologues; breakpoints are number NM_013986 version 3; former exon 7 in indicated by arrows. sequence with accession number X66899) is fused to exon 2 of YY1 (nucleotide 1160 accession Genes involved and number NM_003403 version 3). The putative proteins EWSR1-YY1 protein would contain the transactivation domain of EWSR1 and the DNA YY1 binding domain of YY1 and thus may act as an Location abnormal transcription factor. 14q32.2 Description DNA / RNA The EWSR1-YY1 fusion gene was detected in 2 so Spans 44.495 kb on plus strand. far mesotheliomas (Panagopoulos et al., 2013).

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 63 Mesothelioma: t(14;22)(q32;q12) in mesothelioma Panagopoulos I

Partial sequence chromatogram showing the fusion of exon 8 of EWSR1 with exon 2 of YY1.

human mesothelioma. Lung Cancer. 2009 May;64(2):140- References 7 Bianchi C, Bianchi T. Malignant mesothelioma: global Takeda M, Kasai T, Enomoto Y, Takano M, Morita K, incidence and relationship with asbestos. Ind Health. 2007 Kadota E, Iizuka N, Maruyama H, Nonomura A. Genomic Jun;45(3):379-87 gains and losses in malignant mesothelioma demonstrated by FISH analysis of paraffin-embedded tissues. J Clin Taniguchi T, Karnan S, Fukui T, Yokoyama T, Tagawa H, Pathol. 2012 Jan;65(1):77-82 Yokoi K, Ueda Y, Mitsudomi T, Horio Y, Hida T, Yatabe Y, Seto M, Sekido Y. Genomic profiling of malignant pleural Panagopoulos I, Thorsen J, Gorunova L, Micci F, Haugom mesothelioma with array-based comparative genomic L, Davidson B, Heim S. RNA sequencing identifies fusion hybridization shows frequent non-random chromosomal of the EWSR1 and YY1 genes in mesothelioma with alteration regions including JUN amplification on 1p32. t(14;22)(q32;q12). Genes Chromosomes Cancer. 2013 Cancer Sci. 2007 Mar;98(3):438-46 Aug;52(8):733-40

Moore AJ, Parker RJ, Wiggins J. Malignant mesothelioma. This article should be referenced as such: Orphanet J Rare Dis. 2008 Dec 19;3:34 Panagopoulos I. Mesothelioma: t(14;22)(q32;q12) in Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, mesothelioma. Atlas Genet Cytogenet Oncol Haematol. Felley-Bosco E. Functional inactivation of NF2/merlin in 2015; 19(1):62-64.

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Deep Insight Section

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation Federica Lo Sardo, Sabrina Strano, Giovanni Blandino Translational Oncogenomic Unit, Regina Elena Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy (FLS, GB), Molecular Chemoprevention Unit, Italian National Cancer Institute "Regina Elena", 00144 Rome, Italy (SS)

Published in Atlas Database: May 2014 Online updated version : http://AtlasGeneticsOncology.org/Deep/HippoKinaseID20125.html DOI: 10.4267/2042/55383 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Hippo signaling transduction pathway is widely conserved through evolution and controls cell growth, homeostasis, apoptosis, commitment, differentiation and senescence. It consists of a conserved kinase cascade whose final targets are the transcriptional coactivator Yorkie (Yki) in Drosophila and the homologues YAP and TAZ in mammals. These transcriptional coactivators are unable to bind DNA per se , and can regulate the activity of their target genes only in association with transcription factors. In Drosophila , Yki associates with the transcription factors Sd and Hth regulating pro-proliferative and anti-apoptotic genes. In mammals instead, YAP/TAZ can associate with several distinct transcription factors. This depends from the type of signals to which cells are subjected, the cell type and the developmental stage. The transcriptional outcome resulting from this association can be either pro-apoptotic or pro-proliferative. Hippo pathway dysregulation has been associated with several pathologic conditions (tissue overgrowth, developmental defects and cancer). In particular, solid tumors show an upregulation or hyperactivation of YAP/TAZ, while several hematologic tumors are associated with YAP downregulation. This might suggest that the Hippo pathway holds the potential to be an attractive target for novel therapeutic approaches for cancer.

Introduction transcription in association with other transcription factors. Hippo signal transduction pathway is an Aberrant regulation of the Hippo pathway is evolutionary conserved pathway, from flies to associated with tissue overgrowth and various types humans, that controls organ size, development, of cancers in mammals (see below). Thus, a major tissue regeneration-homeostasis and stem cell self- comprehension of the mechanisms at the basis of renewal through the regulation of cell proliferation, YAP/TAZ upstream regulation and downstream cell commitment and apoptosis. Components of the transcriptional response could also be relevant for pathway include membrane associated proteins that the characterization of prognostic factors in cancer sense cell polarity, cell density and mechanical and for the development of novel anti-cancer cues, that in turn activate a cascade of kinases therapies. whose final target is the transcriptional coactivator Yorkie (Yki) in Drosophila , or its mammalian Hippo pathway core components counterparts Yes Associated Protein (YAP) and The core components of the Hippo pathway were Transcriptional coactivator with PDZ-binding motif firstly discovered in Drosophila melanogaster by (TAZ, also called WWTR1). These factors are mosaic genetic screens which showed a strong unable to bind DNA per se , but can regulate overgrowth phenotype shared by loss-of-function

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 65 The Hippo Kinase Pathway: a master regulator of proliferation, Lo Sardo F, et al. development and differentiation

mutants. Based on these findings, the Hippo Moreover, YAP and TAZ are at the crossroad pathway had been defined as an oncosuppressor between several other signalling pathways as Wnt, pathway. In parallel, homologous components of Tgf β and Notch (reviewed in Barry and Camargo, the pathway were discovered in other organisms, 2013). Conversely, Hippo pathway core including mammals (reviewed in Varelas and components may be involved in cell cycle control Wrana, 2012). Some of them are able to rescue independently of YAP/TAZ regulation. For mutant phenotypes in flies (Lai et al., 2005; Tao et example, Mst1 has been shown to promote al., 1999; Wu et al., 2003). The Hippo pathway core apoptosis in injuried cardiomiocytes independently components are listed in table 1 and schematically of YAP phosphorylation (Maejima et al., 2013). In represented in Figure 1. this case, Mst1 has been shown to phosphorylate They include two serine/threonine kinases beclin1, a protein that alternatively binds Atg14L- associated with adaptor proteins: the first is the Vps34 or Bcl-2 protein. In normal conditions, STE20 kinase Hippo (Hpo) with the adaptor protein beclin1 complexes with Atg14L-Vps34 to promote Salvador (Sav) (MST1/2 and Sav1 in mammals) autophagy, a process required for the recycling of (Callus et al., 2006; Harvey et al., 2003; Jia et al., macromolecular proteins and damaged organelles. 2003; Kango-Singh et al., 2002; Pantalacci et al., Meanwhile, Bcl-2 sequesters Bax and inhibits 2003; Tapon et al., 2002; Udan et al., 2003; Wu et apoptosis. Mst1 phosphorylates Beclin1 at Thr108 al., 2003), and the second is the NDR kinase Warts during cellular stress. This causes Beclin1 (Wts) associated with the scaffold protein Mats, dissociation from Atg14L-Vps34 and its association (Lats1/2 associated with Mob1 in mammals) with Bcl-2 that is no more able to sequester Bax. (Callus et al., 2006; Chan et al., 2005; Praskova et This in turn leads to apoptosis. al., 2008; Wu et al., 2003). Drosophila Hpo and Upstream regulators of Hippo mammalian MST1/2 directly bind Sav protein and are able to phosphorylate and activate Sav itself and pathway core components Mats (Sav1 and Mob1 mammalian counterparts). Proteins involved in cell junction, cell polarity and Drosophila Mats and mammalian Mob1 interact G-protein-coupled receptor (GPCR) signalling are with and phosphorylate Wts and Lats1/2, upstream regulators of the core Hippo pathway. respectively. Wts-Mats and Lats1/2-Mob These proteins regulate YAP/TAZ nuclear activity phosphorylate in turn specific residues of the in response to both mechanical and biochemical transcriptional coactivator Yki and its mammalian stimuli originated from the extracellular matrix counterparts YAP and TAZ. Yki and YAP/TAZ (ECM). phosphorylation result in their cytoplasmic Cell junction/cell polarity: in vivo, epithelial cells sequestration via 14-3-3 binding (Dong et al., 2007; are in contact each another through specialized Haoet al., 2008; Kanai et al., 2000; Lei et al., 2008; cellular junctions, forming sheets that line the Vassilev et al., 2001; Zhao et al., 2007), which surface of the animal body and internal cavities (for inhibits TAZ/YAP nuclear functions as example digestive and circulatory cavities). These transcriptional coactivators, while promoting their cells are oriented in the space with an apical-basal cytoplasmic role (Varelas et al., 2010) or their polarity: the apical membrane is oriented to the proteasomal degradation (Liu et al., 2010; Zhao et outside surface of the body, or the lumen of internal al., 2010). cavities, and the basolateral membrane is oriented It is becoming clear that not only Hippo pathway away from the lumen. Polarity proteins associate core kinases are able to regulate YAP and TAZ with junction proteins in order to contribute to their nuclear activity. For example, recently it has been proper localization and assembly and thereby to the shown that SIRT1 protein is able to activate YAP2 functional organization of the tissues. isoform by deacetylation in hepatocellular carcinoma cells (HCC) (Mao et al., 2014).

Table 1: Hippo pathway core components

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 66 The Hippo Kinase Pathway: a master regulator of proliferation, Lo Sardo F, et al. development and differentiation

Figure 1. Schematic representation of Hippo pathway core components, their upstream regulators and transcriptional outcome in Drosophila (left) and mammals (right). In figure1, the Extracellular Matrix (ECM), the cytoplasm and the nucleus of cells are represented. Proteins are represented in various colours, with homologous components between Drosophila and mammals represented with the same colour. Black arrows indicate activation, while blunt lines indicate inhibition. Light blue arrows indicate phosphorylation of proteins by kinases. Orange balls indicate phosphorylation sites of target proteins. The Hippo pathway core kinase cassette is represented inside a black rectangle. For simplicity, junction proteins and polarity proteins are not represented by the specific Drosophila or mammalian subunits. In general, even if they are represented by different complexes in Drosophila or mammals, either homologous or not, they inhibit Yki and YAP/TAZ nuclear activity by sequestering them at the apical membrane or by interacting with and activating the Hippo pathway core kinases (represented in the black rectangle) that in turn inhibit Yki and YAP/TAZ nuclear activity. In mammals, GPCR signalling and mechanical stress coming from the ECM activate Rho GTPase that in turn stabilizes the actin cytoskeleton thus inhibiting Hippo pathway core kinases (and activating YAP/TAZ nuclear activity). In the nucleus, Drosophila Yki interacts with Sd or Hth transcription factors and activates pro-proliferative and anti-apoptotic genes. Mammalian YAP and TAZ instead interact with several different transcription factors (see also table 3) and the resulting transcriptional outcome may be either pro-proliferative or pro-apoptotic. This might depend from the incoming signals to which cells are exposed and from the specificity of the associated transcription factor.

The Kibra complex, conserved in Drosophila and in MPDZ, PATJ, PALS1, LIN7C, PTPN14, ZO-1, a- mammals, represents an example of apical proteins β-catenin and E-cadherin have been identified as involved in Hippo pathway regulation. It recruits interacting partners or regulators of Hippo pathway Hippo pathway core components like Hpo and Sav core components (Kim et al., 2011; Liu X et al., to the apical plasma membrane for activation, thus 2013; Oka et al., 2010; Remue et al., 2010; inhibiting YAP/TAZ nuclear activity and tissue Schlegelmilch et al., 2011; Zhao et al., 2011). growth (Genevet et al., 2010; Yu et al., 2010). Also In general, these proteins negatively regulate the Crumbs polarity complex, the Scribble complex YAP/TAZ nuclear function by sequestering and Par3 polarity complex have been shown to be YAP/TAZ to the apical plasma membrane, thus negative regulators of YAP and TAZ nuclear excluding them from the nucleus, and by interacting function (Chen et al., 2010; Gurvich et al., 2010; with and activating hippo pathway core kinases. Ling et al., 2010; Robinson et al., 2010; Varelas et This in turn inhibits YAP and TAZ nuclear function al., 2010). Other polarity proteins as Ajuba and by phosphorylation (Genevet et al., 2010; Varelas LKB1 have been shown to negatively regulate YAP et al., 2010; Yu et al., 2010; Zhao et al., 2011). and TAZ nuclear function (Das Thakur et al., 2010; Indeed, disruption of cellular junctions or Nguyen et al., 2013). Moreover, many cell junction downregulation of cell polarity/cell junction associated proteins, such as angiomotin (AMOT), proteins leads to YAP/TAZ activation (Chen et al.,

Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 67 The Hippo Kinase Pathway: a master regulator of proliferation, Lo Sardo F, et al. development and differentiation

2010; Cordenonsi et al., 2011; Dupont et al., 2011; ECM contact area and a low mechanical stress. Varelas et al., 2010). Thus, YAP and TAZ nuclear (Dupont et al., 2011; Wada et al., 2011; Zhao et al., function is inhibited by cell contact to finely tune 2012; Zhao et al., 2007) . YAP and TAZ are not the proliferation of cells within a tissue and an only mechanosensors, but also mechanoeffectors organ during physiological tissue-organ growth and because, once activated, they are able to regulate in regeneration. However, there are few exception to turn genes involved in extracellular matrix this rule: NPHP4 (nephronophthisis 4) can interact remodelling (Calvo et al., 2013). with and inhibit Lats1 (Habbig et al., 2011) and It is still not completely clear how mechanical and ZO-2 (zona occludens-2) can induce YAP nuclear biochemical cues experienced by the cell are linked localization (Oka et al., 2010). The regulation of with YAP and TAZ activity. It has been shown that Hippo pathway by apical-basal polarity and cell both RHO GTPases and the actin cytoskeleton are junction is largely conserved in Drosophila and able to transduce these upstream signals to YAP mammals, even if not all the proteins are conserved and TAZ. In particular, F-actin stabilization and between flies and vertebrates (Bossuyt et al., 2014). RHO-GTPase activation (depending on the Biochemical signals: very recently, several groups activated G α protein) are able to activate have shown that diffusible signals and metabolites YAP/TAZ, while F-actin destabilization determines like LPA, S1P, thrombin and statins regulate YAP/TAZ inhibition. However, the gap between YAP/TAZ function (Miller et al., 2012; Mo et al., YAP and TAZ and these upstream transducers 2012; Sorrentino et al., 2014; Yu et al., 2012). LPA, remains to be fulfilled. S1P and thrombin activate G-protein coupled receptor (GPCR) which usually activate YAP-TAZ effectors and their downstream signalling through heterotrimeric G transcriptional targets proteins that in turn activate the mediator Rho YAP mRNA is ubiquitously expressed in a wide GTPase. Depending on which G α protein is range of mammalian tissues, with the exception of activated, YAP and TAZ may be either activated or peripheral blood leukocytes (Komuro et al., 2003), repressed. In fact, G α12/13 -, G αq/11 -, or G αi/o -coupled it is expressed in all developmental stages from signals induce YAP/TAZ activity, whereas G αs- blastocyst to perinatal and it is necessary for a coupled signals repress YAP/TAZ activity (Mo et correct and vital embryonic development. TAZ al., 2012; Yu et al., 2012). Rho GTPase are also instead shows a later onset, it is present in all the regulated by mevalonate pathway. Recently in embryonic stages with the exception of blastocyst Sorrentino lab it has been shown that statins, by stage (Morin-Kensicki et al., 2006). YAP and TAZ inhibiting the mevalonate biosynthesis, prevent Rho per se are not able to bind DNA, but they regulate GTPase activation and thus Yki and YAP/TAZ gene targets expression (either by activation or nuclear function (Sorrentino et al., 2014). repression) through interaction with transcription Mechanical cues: in vivo, cells are subjected to factors in a tissue and development specific mechanical stimulation coming from neighbouring manner. cells, the ECM and surrounding biological fluids. By now, several YAP and TAZ interacting proteins These signals influence cell proliferation and have been characterized among which some are migration, and cytoskeletal changes are at the basis able to sequester or post-transcritpionally modify of cellular responses to these mechanical stimuli. It YAP and TAZ (table2) (Chan et al., 2011; Chen has been recently shown that YAP and TAZ are and Sudol, 1995; Espanel and Sudol, 2001; Howell regulated by changes in the actin cytoskeleton in et al., 2004; Hsu and Lawlor, 2011; Koontz et al., response to mechanical cues experienced by the 2013; Mohler et al., 1999; Rosenbluh et al., 2012; cell. In particular, cell adhesion, cell geometry, cell Sudol, 1994; Tsutsumi et al., 2013), others are shape, cell suspension and extracellular matrix transcriptional regulators (table3) (Cui et al., 2003; stiffness have been shown to regulate YAP/TAZ Di Palma et al., 2009; Ferrigno et al., 2002; Hong et nuclear activity in different experimental reports. al., 2005; Hsu and Lawlor, 2011; Jeong et al., 2010; When cells are grown at low cell density, or on a Kang et al., 2009; Murakami et al., 2005; Wang J et stiff extracellular substrate, or also on a large al., 2013; Xiao et al., 2013; Yagi et al., 1999). All adhesive island, conditions where the cell-ECM the components of the Hippo pathway, from the contact area is broad and the cytoskeleton is membrane associated proteins to the cytoplasmic subjected to a stronger mechanical stimulation YAP kinase cascade to the final effectors YAP and TAZ, and TAZ are predominantly localized in the are characterized by specific protein-protein nucleus. Conversely, YAP/TAZ effectors interaction domains, among which the most translocate to the cytplasm in response to high common are WW domain and the similar SH3 cellular density/cell contact, on a soft extracellular domain, able to bind short peptides that are prolin- substrate or on micropatterned small islands, rich and often terminate with Tyrosine (Y), named conditions in which the cell experience a small cell- PpxY motifs (Sudol and Hunter, 2000).

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Table 2: YAP/TAZ interactors in mammals (regulative proteins)

There are two major YAP splicing variants with proliferation/survival or apoptosis, like TEAD one (YAP1) or two (YAP2) WW domains, but (Chan et al., 2009; Mahoney et al., 2005; Ota and recently, eight different spliced mRNA isoforms of Sasaki, 2008; Vassilev et al., 2001; Zhang et al., YAP1 gene have been characterized and identified 2009; Zhao et al., 2008) and p73 transcription in a panel of human tissues (Gaffney et al., 2012). factors, (Strano et al., 2001) or are components of The different splicing variants of YAP, the different other signalling pathways as Wnt, EGFR, JAK/Stat, post-transcriptional modifications of YAP and BMP-TGFbeta involved in embryonic development TAZ, and the different chromatin state of target and adult tissue homeostasis. For example, it has genes may select different repertoires of proteins in been shown that YAP/TAZ interact with Smad transcriptional complexes and affect the gene proteins (Smad1, Smad2, Smad3) to enhance the expression program in a developmental and tissue- transcription of genes responsive to BMP-TGFbeta specific manner (Beyer et al., 2013; Reginensi et signalling (Alarcon et al., 2009; Schlegelmilch et al., 2013; Slattery et al., 2013). al., 2011; Varelas et al., 2010). Other transcriptional The transcription factors with which YAP and TAZ targets are represented by components of the Hippo cooperate are directly involved in control of cell pathway.

Table 3: YAP/TAZ interactors in mammals (transcription factors).

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Table 4: Tumor tissues or tumor cell lines where YAP/TAZ are overexpressed or hyperactivated.

The dual role of YAP as an YAP as an oncogene oncoprotein or an There are several evidences supporting a pro- oncosuppressor proliferative and pro-oncogenic role of YAP (and A lot of studies supported the functional TAZ) in mammalian systems. In humans, YAP is conservation of the core Hippo pathway present in the 11q22 amplicon that is amplified in a components between Drosophila and mammals in lot of solid tumors (Baldwin et al., 2005; Bashyam the control of cell proliferation. et al., 2005; Dai et al., 2003; Hermsen et al., 2005; When Hippo kinase pathway is inactive, YAP and Imoto et al., 2002; Imoto et al., 2001; Lambros et TAZ enter the nucleus and affect transcription of al., 2005; Overholtzer et al., 2006; Snijders et al., different sets of target genes in a tissue and 2005; Weber et al., 1996) (Table 4). developmental specific manner (Beyer et al., 2013; The syntenic chromosomal region in mouse Slattery et al., 2013). contains YAP gene that is amplified in mammary Increasing evidences showed that the transcriptional and liver tumors (Overholtzer et al., 2006; Zender outcome in response to YAP/TAZ activation can be et al., 2006). opposite. Ectopic expression or hyperactivation of YAP In mammals, it has been shown that YAP promotes cell growth and induces oncogenic transcriptional coactivator can function either as an transformation and epithelial-mesenchimal oncogene, or as a tumor suppressor, depending on transition (EMT) that is often associated with the signals to which cells are subjected and on the metastasis (Lamar et al., 2012; Lau et al., 2014; transcription factors with which YAP is associated. Nallet-Staub et al., 2013; Overholtzer et al., 2006; The emerging and intriguing dual role of YAP and Zhao et al., 2009; Zhao et al., 2008). the mechanisms determining the two exclusive In mouse, transgenic YAP overexpression or liver- cellular responses (pro-proliferative or pro- specific knockout of Mst1/2 and Sav1 increases the apoptotic) are still not entirely understood as they number of stem/progenitor cells and determines were built on classic studies performed in different liver overgrowth in a reversible manner, ultimately cell types and tissues. leading to hepatocellular carcinoma (HCC) Here, we will discuss experimental evidences (Camargo et al., 2007; Dong et al., 2007; Lee et al., showing YAP as an oncogene or as an 2010; Lu et al., 2010; Song et al., 2010; Zhou et al., oncosuppressor. 2009).

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Consistently, a lot of human cancers show shown to be phosphorylated by c-Abl that stabilizes overexpression or hyperactivation of nuclear YAP both YAP and p73 and increases YAP/p73 or TAZ or downregulation of Lasts1/2, Mst1/2 or interaction (Levy et al., 2008). On the other hand, Sav1 function (Dong et al., 2007; Hall et al., 2010; p73-YAP interaction is inhibited upon Akt- Jiang et al., 2006; Matsuura et al., 2011; Muramatsu mediated YAP phosphorylation (Basu et al., 2003). et al., 2011; Nallet-Staub et al., 2013; Quan et al., p73 is post-transcriptionally stabilized by YAP 2014; Seidel et al., 2007; Steinhardt et al., 2008; Su binding that competes with the E3 ubiquitin ligase et al., 2012; Takahashi et al., 2005; Wang L et al., ITCH, thereby preventing proteasomal degradation 2013; Wang et al., 2012; Wang et al., 2010; of p73 (Levy et al., 2007). YAP binding also Wierzbicki et al., 2013; Xu et al., 2011; Xu et al., induces p73 acetylation and transcriptional activity 2009; Yuen et al., 2013; Zender et al., 2006; Zhao by recuiting the p300 acetyltranferase to target et al., 2007; Zhou Z et al., 2011) see also table 4. genes (Strano et al., 2005). Another Moreover, overexpression or hyperactivation of oncosuppressor, PML (Promyelocytic leukemia YAP and TAZ have been associated with poor protein) has been shown to act together with YAP prognosis and shorter survival times for patients in and p73 as a mediator onto several proapoptotic several human cancers (Hall et al., 2010; Liu JH et target genes following DNA damage by physically al., 2013; Muramatsu et al., 2011; Wang et al., interacting with both p73 and YAP (Bernassola et 2010; Xu et al., 2009; Zhang et al., 2011). It has al., 2004; Lapi et al., 2008). PML is a key been also shown that Mst1/2 and Sav1 knockout, or component and organizer of nuclear compartments YAP activation expanded the stem and the termed nuclear bodies (NBs) implicated in progenitor cell population in the intestine and in the processes such as transcriptional regulation, skin in mouse (Lee et al., 2008; Schlegelmilch et genome stability, response to viral infection, al., 2011; Zhou D et al., 2011). YAP has been metabolism, apoptosis, and cell cycle control shown to contribute also to the expansion of (reviewed in Gamell et al., 2014). It has also been neuroprogenitor cells (Cao et al., 2008). In addition, proposed that PML partially collaborates with YAP YAP has been found to be upregulated in mouse and p73 in the proapoptotic response induced by Embryonic Stem cells (mES) and in induced DNA damage by several self-reinforcing pluripotent stem cells (iPS) and to contribute to mechanisms. First, YAP requires PML and NBs their stemness by binding and activating a large localization to coactivate p73 and, conversely, YAP number of genes known to be important for stem and p73 are required for PML accumulation and cell maintenance (Lian et al., 2010). PML-NB formation in response to DNA damage. TAZ is overexpressed in breast cancer stem cells Second, PML stabilizes YAP from proteasomal and is required to maintain their self-renewal degradation by inducing its sumoylation and its capacity, tumorigenicity and ability to promote the recruitment into PML-nuclear bodies, where it formation of metastasis (Bartucci et al., 2014; Chan collaborates with YAP and p73 onto target genes. et al., 2008; Cordenonsi et al., 2011). Moreover, Third, PML itself is a transcriptional target of YAP- YAP and TAZ have been recently found to be p73-PML complex (Lapi et al., 2008; Strano et al., upregulated in mouse wounds and to be required for 2005). wound closure (Lee et al., 2014). Based on these Interestingly, it has been shown an important role results, YAP and TAZ are defined as oncogenes for YAP in the regulation of cellular senescence in and as "stemness genes" (Ramalho-Santos et al., a functional cooperation with PML and p53 (Fausti 2002). et al., 2013; Xie et al., 2013). TEAD transcription factors guides YAP and TAZ Finally, while in many solid cancers YAP behaves onto pro-proliferative genes (Chan et al., 2009; as an oncogene and is upregulated or hyperactivated Lamar et al., 2012; Mahoney et al., 2005; Zhang et (see above), in hematologic malignancies, including al., 2009; Zhao et al., 2008). lymphomas, leukemias and multiple myelomas YAP as a tumor suppressor YAP is deleted or downregulated. Lower YAP expression level correlates with poorer prognosis We originally showed that the tumor suppressor and shorter survival of patients (Cottini et al., p73 protein, which belongs to the p53 family, has 2014). In the context of hematologic malignancies, been shown to guide YAP onto pro-apoptotic YAP downregulation is a mechanism by which targets. These findings together with other cells escape apoptosis in the presence of DNA evidences from diverse labs indicated that YAP damage. In fact, in normal hematologic cells YAP might behave as a tumor suppressor, in particular is phosphorylated by c-abl that stabilizes YAP/p73 upon DNA damage signalling and serum interaction and increases their transcriptional deprivation (Lapi et al., 2008; Oka et al., 2008; activity onto pro-apoptotic genes in the presence of Strano et al., 2005; Strano et al., 2001; Yuan et al., DNA damage (Levy et al., 2007; Levy et al., 2008), 2008). p73-YAP interaction is increased upon DNA while in malignant cells, where YAP is damage (Strano et al., 2005), where it has been downregulated or absent, the c-Abl/p73/YAP axis

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is disrupted (Cottini et al., 2014). Collectively, Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. these observations do not classify YAP as a real TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized tumor suppressor, but as a transcriptional co- in the cytoplasm. Genes Dev. 2001 May 15;15(10):1229- activator that can directly or indirectly regulate 41 different tumor suppressor pathways (as p53 family Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, or PML). Camonis J, Atfi A, Mauviel A. Yes-associated protein A better understanding of the role of the Hippo (YAP65) interacts with Smad7 and potentiates its inhibitory pathway in tumorigenesis assessed in different activity against TGF-beta/Smad signaling. 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Nuclear CDKs drive Dev. 2010 Jun 1;24(11):1106-18 Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009 Nov 13;139(4):757-69 Lee KP, Lee JH, Kim TS, Kim TH, Park HD, Byun JS, Kim MC, Jeong WI, Calvisi DF, Kim JM, Lim DS. The Hippo- Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W. Salvador pathway restrains hepatic oval cell proliferation, TEADs mediate nuclear retention of TAZ to promote liver size, and liver tumorigenesis. Proc Natl Acad Sci U S oncogenic transformation. J Biol Chem. 2009 May A. 2010 May 4;107(18):8248-53 22;284(21):14347-58 Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Pan D. The apical transmembrane protein Crumbs Cristofaro T, Del Prete D, Pappalardo A, Mascia A, Zannini functions as a tumor suppressor that regulates Hippo M. TAZ is a coactivator for Pax8 and TTF-1, two signaling by binding to Expanded. Proc Natl Acad Sci U S transcription factors involved in thyroid differentiation. Exp A. 2010 Jun 8;107(23):10532-7 Cell Res. 2009 Jan 15;315(2):162-75 Liu CY, Zha ZY, Zhou X, Zhang H, Huang W, Zhao D, Li T, Kang HS, Beak JY, Kim YS, Herbert R, Jetten AM. Glis3 is Chan SW, Lim CJ, Hong W, Zhao S, Xiong Y, Lei QY, associated with primary cilia and Wwtr1/TAZ and Guan KL. The hippo tumor pathway promotes TAZ implicated in polycystic kidney disease. Mol Cell Biol. 2009 degradation by phosphorylating a phosphodegron and May;29(10):2556-69 recruiting the SCF{beta}-TrCP E3 ligase. J Biol Chem. Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe 2010 Nov 26;285(48):37159-69 SW, Poon RT, Luk JM. Yes-associated protein is an Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, independent prognostic marker in hepatocellular Halder G, Finegold MJ, Lee JS, Johnson RL. Hippo carcinoma. 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YAP2 and ZO-2 are PDZ domain-dependent, and regulate pathogenesis of high-grade clear cell renal cell carcinoma. YAP2 nuclear localization and signalling. Biochem J. 2010 BMC Cancer. 2011 Dec 20;11:523 Dec 15;432(3):461-72 Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol Remue E, Meerschaert K, Oka T, Boucherie C, M, Shimada Y, Tsuda H, Kawano T, Inazawa J. YAP is a Vandekerckhove J, Sudol M, Gettemans J. TAZ interacts candidate oncogene for esophageal squamous cell with zonula occludens-1 and -2 proteins in a PDZ-1 carcinoma. Carcinogenesis. 2011 Mar;32(3):389-98 dependent manner. FEBS Lett. 2010 Oct 8;584(19):4175- 80 Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs Brummelkamp TR, Camargo FD. Yap1 acts downstream regulates Salvador/Warts/Hippo signaling in Drosophila via of α-catenin to control epidermal proliferation. Cell. 2011 the FERM-domain protein Expanded. 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Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox 2010 Dec 14;19(6):831-44 SB, Bowtell DD, Harvey KF. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. oncogene. Oncogene. 2011 Jun 23;30(25):2810-22 Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL. cancer. Cancer Sci. 2010 May;101(5):1279-85 Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 2011 Jan Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. Kibra 1;25(1):51-63 functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, Dev Cell. 2010 Feb 16;18(2):288-99 Dawson D, Willis JE, Markowitz SD, Camargo FD, Avruch J. Mst1 and Mst2 protein kinases restrain intestinal stem Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. 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Varelas X, Wrana JL. Coordinating developmental Slattery M, Voutev R, Ma L, Nègre N, White KP, Mann RS. signaling: novel roles for the Hippo pathway. Trends Cell Divergent transcriptional regulatory logic at the intersection Biol. 2012 Feb;22(2):88-96 of tissue growth and developmental patterning. PLoS Genet. 2013;9(9):e1003753 Wang X, Su L, Ou Q. Yes-associated protein promotes tumour development in luminal epithelial derived breast Tsutsumi R, Masoudi M, Takahashi A, Fujii Y, Hayashi T, cancer. Eur J Cancer. 2012 May;48(8):1227-34 Kikuchi I, Satou Y, Taira M, Hatakeyama M. YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, function. Dev Cell. 2013 Sep 30;26(6):658-65 Zhao J, Yuan H, Tumaneng K, Li H, Fu XD, Mills GB, Guan KL. Regulation of the Hippo-YAP pathway by G- Wang J, Ma L, Weng W, Qiao Y, Zhang Y, He J, Wang H, protein-coupled receptor signaling. 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Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1) 76 The Hippo Kinase Pathway: a master regulator of proliferation, Lo Sardo F, et al. development and differentiation

HS. YAP and TAZ regulate skin wound healing. J Invest cell carcinoma: impact on keratinocyte proliferation and Dermatol. 2014 Feb;134(2):518-25 stromal cell activation. Am J Pathol. 2014 Apr;184(4):937- 43 Mao B, Hu F, Cheng J, Wang P, Xu M, Yuan F, Meng S, Wang Y, Yuan Z, Bi W. SIRT1 regulates YAP2-mediated Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, cell proliferation and chemoresistance in hepatocellular Mano M, Dupont S, Manfrin A, Ingallina E, Sommaggio R, carcinoma. Oncogene. 2014 Mar 13;33(11):1468-74 Piazza S, Rosato A, Piccolo S, Del Sal G. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Cell Biol. 2014 Apr;16(4):357-66 Bataille V, Sudol M, Herlyn M, Mauviel A. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in This article should be referenced as such: cutaneous melanoma. J Invest Dermatol. 2014 Jan;134(1):123-32 Lo Sardo F, Strano S, Blandino G. The Hippo Kinase Pathway: a master regulator of proliferation, development Quan T, Xu Y, Qin Z, Robichaud P, Betcher S, Calderone and differentiation. Atlas Genet Cytogenet Oncol K, He T, Johnson TM, Voorhees JJ, Fisher GJ. Elevated Haematol. 2015; 19(1):65-77. YAP and its downstream targets CCN1 and CCN2 in basal

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